1.A.1 The Voltage-gated Ion Channel (VIC) Superfamily

Proteins of the VIC family are ion-selective channel proteins found in a wide range of bacteria, archaea, eukaryotes and viruses. They are often homo- or heterooligomeric structures with several dissimilar subunits (e.g., α1-α2-δ-β Ca2+ channels, αβ1β2 Na+ channels or (α)4-β K+ channels), but the channel and the primary receptor is usually associated with the α (or α1) subunit. Functionally characterized members are specific for K+, Na+ or Ca2+. The K+ channels usually consist of homotetrameric structures with each α-subunit possessing six transmembrane spanners (TMSs). Many voltage-sensitive K+ channels function with β-subunits that modify K+ channel gating. These nonintegral β-subunits are oxidoreductases that coassemble with the tetrameric α-subunits in the endoplasmic reticulum and remain tightly adherent to the α-subunit tetramer. The high resolution β-subunit structure is available (Gulbis et al., 1999). Non-homologous β-subunits of Na+ and Ca2+ channels function in regulation (Hanlon and Wallace, 2002).  Voltage-gated Ca2+ (Cav) channels have 4 subunits which have all been examined phylogenetically from evolutionary standpoints (Moran and Zakon 2014).  Members of the VIC (1.A.1), RIR-CaC (2.A.3) and TRP-CC (1.A.4) Families have similar transmembrane domain structures, but very different cytosolic doman structures (Mio et al. 2008).  How membrane proteins sense voltage (the membrane potential) has been reviewed (Bezanilla 2008). The involvement of glycosylation in the function and expression of these channels has also been reviewed (Lazniewska and Weiss 2017).  Ion channel disfunction in semen may account for male infertility (Carkci et al. 2017). The spatial expression of K+ channels in mammalian cells has been reviewed (Capera et al. 2019).  Large-conductance Ca2+- and voltage-gated K+ channels form and break interactions with membrane lipids during each gating cycle (Tian et al. 2019).

The α-subunits of the Ca2+ and Na+ channels are usually four times as large as the K+ channel α-subunits and possess 4 units, each with 6 TMSs separated by a hydrophilic loop, for a total of 24 TMSs. These large channel proteins form heterotetrameric-unit structures equivalent to the homotetrameric structures of most K+ channels. All four units of the Ca2+ and Na+ channels are homologous to the single unit in the homotetrameric K+ channels. Some Na+ and Ca2+ channels are half sized with two 6 TMS units, forming dimers (see subfamily 1.A.1.11).  Ion flux via the eukaryotic channels is generally controlled by the transmembrane electrical potential (hence the designation, voltage-sensitive) although some are controlled by ligand or receptor binding. The 6 TMS VIC family members have a gating charge transfer center in the voltage sensors (Tao et al., 2010).  Structural aspects of the calcium channels, revealing the architectural features that underlie their feedback regulatory mechanisms have been reviewed (Minor and Findeisen 2010).  The evolution of VIC superfamily channels with a special emphasis on the metazoan lineage has been reviewed (Moran et al. 2015).  Evolutioin of the 4 TMS voltage sensor has also been reviewed (Freites and Tobias 2015).  Blockade of Na+ channels (NaVs) enables control of pathological firing patterns that occur in a diverse range of conditions such as chronic pain, epilepsy, and cardiac arrhythmias (Bagal et al. 2015).

Voltage-gated sodium channels (VGSCs) are heteromeric transmembrane protein complexes. Nine homologous members, SCN1A-11A, make up the VGSC gene family. Sodium channel isoforms display a wide range of kinetic properties endowing different neuronal types with distinctly varied firing properties. Among the VGSCs isoforms, Nav1.7, Nav1.8 and Nav1.9 are preferentially expressed in the peripheral nervous system. These isoforms are known to be crucial in the conduction of nociceptive stimuli with mutations in these channels thought to be the underlying cause of a variety of heritable pain disorders (Kanellopoulos and Matsuyama 2016). Na+ channels are associated with neuropathic pain (Devor 2006). A 4 x 6 TMS template is shared among voltage-gated sodium (Nav1 and Nav2) and calcium channels (Cav1, Cav2, and Cav3) and leak channel (NALCN) plus homologs from yeast, different single-cell protists (heterokont and unikont) and algae (green and brown) (Fux et al. 2018). The asymmetrically arranged pores of 4x6 TMS channels allows for a changeable ion selectivity via a single lysine residue change in the high field strength site of the ion selectivity filter in Domains II or III.  Modeling has provided clues for rational drug design (Montini et al. 2018). Mexiletine, a class Ib antiarrhythmic drug, is used clinically to reduce or prevent myotonia and is neuroprotective. It binds to the upper part of the pore in the open state and lower part in the closed state. High-affinity binding in the open states of Nav1.4 and Nav1.5 is caused by a pi-pi interactions with Phe (Nakagawa et al. 2019).

There are four known K+ channel families in mammals (humans): (1) The voltage dependent K+ channels designated as Kv channels, which consist of twelve subfamilies. (2) The two pore domain channels, the K2P, which consist of fourteen subfamilies. (3) The calcium activated K+ channels, KCa channels, which consist of five subfamilies. (4) The inward rectifier K+ channels, the Kir, which include seven subfamilies, designated Kir 1 - Kir 7 with fifteen members. G-protein coupled receptors (GPCRs) modulate a number of K+ channels. The most intensively studied and characterized are the K+ inward rectifier Kir 3 subfamily (Kir3.1-Kir3.4) (Gohar, 2006).  The Kv channels' voltage dependences are set in part by charged amino-acid residues of the extracellular linkers which electrostatically affect the charged amino-acid residues of the voltage sensor, S4 (Elinder et al. 2016). Kv-type channels can be consdered to be allosteric machines in which gating may be dynamically influenced by some long-range interactional/allosteric mechanisms (Barros et al. 2019). Molecular dynamics simulations directly predict the response of a voltage-gated K+ channels within a phospholipid bilayer membrane to applied transmembrane voltages (Tronin et al. 2019).

BK-type Ca2+ channels and lipid phosphatases have a transmembrane voltage sensor domain (VSD) that moves in response to physiological variations of the membrane potential to control their activities. However, VSD movements and coupling to the channel or phosphatase activities may differ depending on various interactions between the VSD and its host molecules (Cui 2010). BK-type voltage, Ca²+ and Mg²+ activated K+ channels contain the VSD and a large cytosolic domain (CTD) that binds Ca²+and Mg²+. VSD movements are coupled to BK channel opening with a unique allosteric mechanism and are modulated by Ca²+ and Mg²+ binding via interactions between the channel pore, VSD and CTD. It is energetically advantageous for the pore to be controlled by multiple stimuli (Cui 2010).

The erg or Kv11 (according to the new nomenclature) is a subfamily of the voltage-dependent K+ channel superfamily and includes three members: Kv11.1 (erg1), Kv11.2 (erg2) and Kv11.3 (erg3) channels. The most studied member of this subfamily is Kv11.1 that regulates the duration of the cardiac action potential. Mutations in this channel have been associated with cardiac arrhythmias and sudden death (Bronstein-Sitton, 2006).

Five types of Ca2+ channels are expressed in the CNS of mammals: The L-type (Cav1), N-type (Cav2.2), P/Q-type (Cav2.1), R-type (Cav2.3), and the T-type (Cav3). Each Cav channel is a multimeric protein composed of a pore forming α1 subunit and the auxiliary β (Cavβ), α2δ and γ subunits. There are four known Cavβ subunits, in addition to four α2δ subunits and eight γ subunits. The best characterized Ca2+ channels that are regulated by GPCRs are the N-type and the P/Q-type which have significant roles in neuronal communication. This mechanism is the basis of synaptic modulation caused by endogenous hormones as well as exogenously applied agents (such as analgesia caused by morphine). The identification of the types of Ca2+ channels that are modulated by GPCRs was enabled by the use of specific toxins: ω-Conotoxin GVIA for the N-type channels and ω-Agatoxin-IVA for the P/Q-type channels. Many Ca2+ channels are regulated by GPCRs (Gohar, 2006). Endodgenous membrane phosphatidylinositol 4,5-biphosphate, PIP2, activates high voltage activated L-, N- and P/Q type Ca2+ channels, and PIP2 depletion inhibits these Ca2+ channels (Suh et al., 2010).

In type-2 diabetes, the tight link between glucose sensing and insulin secretion is impaired due to mutations in a KATP channel. K+ channels that are sensitive to ATP are plasma membrane protein complexes composed of four Kir6.2 (KCNJ11) pore-forming subunits surrounded by four SUR1 (sulphanylurea receptor, of the ABC superfamily) auxiliary subunits. These protein complexes sense the amount of glucose entering a beta cell in the pancreas since the activity of KATP channels depends on the amount of ATP in the cytoplasm, which in turn depends on the amount of glucose absorbed by the beta cell. The activity of KATP channels is negatively correlated to the amount of ATP. KATP channels are the main channels that are open during resting conditions. Closure of KATP channels by increased ATP concentrations leads to membrane depolarization, which causes opening of voltage dependent Ca2+ (Cav) channels, leading to Ca2+ influx. The main Cav channels that control insulin secretion are L-type channels of the Cav1 subfamily (Cav1.2 and/or Cav1.3) (Cherki et al., 2006).

Ion channelopathies are inherited diseases in which alterations in control of ion conductance through the central pore of ion channels impair cell function, leading to periodic paralysis, cardiac arrhythmia, renal failure, epilepsy, migraine and ataxia (Kullmann and Waxman, 2010). However, Sokolov et al. (2007) have shown that, in contrast with this well-established paradigm, three mutations in gating-charge-carrying arginine residues in an S4 segment of NaV1.4 (TC #1.A.1.10.4) that cause hypokalaemic periodic paralysis induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle NaV1.4 channel. This 'gating pore current' is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor. It has similar permeability to Na+, K+ and Cs+, but the organic monovalent cations tetraethylammonium and N-methyl-D-glucamine are much less permeant. The inorganic divalent cations Ba2+, Ca2+ and Zn2+ are not detectably permeant and block the gating pore at millimolar concentrations. The results reveal gating pore current in naturally occurring disease mutations of an ion channel and show a clear correlation between mutations that cause gating pore current and hypokalemic periodic paralysis. The involvement of channel protein in neurodegenerative disorders has been reviewed (Kumar et al. 2016).

Several putative K+-selective channel proteins of the VIC family have been identified in prokaryotes. The structures of two of them, the 2 TMS voltage-insensitive KcsA K+ channel of Streptomyces lividans and the 6 TMS KvAP voltage-sensitive K+ channel of Aeropyrum pernix, have been solved to 3.2 Å resolution (TC #1.A.1.1.1 and 1.A.1.17.1, respectively) (Cuello et al., 2004; Doyle et al., 1998; Jiang et al., 2003a,b; Ruta et al., 2003). Both proteins possess four identical subunits, each with two transmembrane helices, arranged in the shape of an inverted teepee or cone, forming the channel. The cone cradles the 'selectivity filter' P domain in its outer end. The narrow selectivity filter is only 12 Å long, whereas the remainder of the channel is wider and lined with hydrophobic residues. The first TMS (S1) is at the contact interface between the voltage sensing and pore domains (Cuello et al., 2004). A large water-filled cavity and helix dipoles stabilize K+ in the pore. The selectivity filter has two bound K+ ions about 7.5 Å apart from each other. Ion conduction is proposed to result from a balance of electrostatic attractive and repulsive forces. Evolutionary relationships between K+ channels and certain K+:cation symporters has been reviewed and discussed (Durell et al., 1999).

KcsA channels twist around the axis of the pore. Conformational changes are prevented by an open-channel blocker, tetrabuthylammonium. Random clockwise and counterclockwise twisting in the range of several tens of degrees originate in the transmembrane domain and are transmitted to the cytoplasmic domain. This twisting motion may play a role in gating (Shimizu et al., 2008). This coupling suggests a mechanical interplay between the transmembrane and cytoplasmic domains.

The open-state conformation of the KcsA K+ channel has been studied using the Monte Carlo normal mode following simulations. Gating involves rotation and unwinding of the TM2 bundle, lateral movement of the TM2 helices away from the channel axis, and disappearance of the TM2 bundle. The gating transition is intrinsically multidimensional and described by a rough free-energy landscape (Delemotte et al. 2015).  The open-state conformation of KcsA exhibits a wide inner vestibule, with a radius approximately 5-7 Å and inner helices bent at the A98-G99 hinge. Computed conformational changes demonstrate that spin labeling and X-ray experiments illuminate different stages in gating: transition begins with clockwise rotation of the TM2 helices ending at a final state with the TM2 bend hinged near residues A98-G99. The concordance between the computational and experimental results provides atomic-level insight into the structural rearrangements of the channel's inner pore (Miloshevsky and Jordan, 2007).

Interconversion between conductive and non-conductive forms of the K+ channel selectivity filter underlies a variety of gating events. Cuello et al. (2010) reported the crystal structure of the Streptomyces lividans K+ channel, KcsA, in its open-inactivated conformation. They investigated the mechanism of C-type inactivation gating at the selectivity filter from channels 'trapped' in a series of partially open conformations. Five conformer classes were identified with openings ranging from 12 Å in closed KcsA to 32 Å when fully open. A correlation was observed between the degree of gate opening and the conformation and ion occupancy of the selectivity filter. A gradual filter backbone reorientation leads first to a loss of the S2 ion binding site and a subsequent loss of the S3 binding site, presumably abrogating ion conduction. 

The archaeal voltage-dependent K+ channel (TC #1.A.1.17.1) has been characterized (Ruta et al., 2003). It exhibits the properties of a classical neuronal K+ channel including structural conservation in the voltage sensor as revealed by specific high affinity tarantula venom toxin binding. This toxin evolved to inhibit animal Kv channels.  The first four transmembrane helices (S1-S4) of any 6 TMS VIC family member, undergoes the first conformational changes in response to membrane voltage variations, and the S4 segment of each domain, which contains several positively charged residues interspersed with hydrophobic amino acids, is located within the membrane electric field and plays an essential role in voltage sensing (Miceli et al. 2015).

Three other bacterial VIC family channels have been characterized functionally. One is the 2 TMS LctB channel of Bacillus stearothermophilus (TC #1.A.1.1.2; Wolters et al., 1999), the second is the 6 TMS Kch channel of E. coli (TC #1.A.1.13.1; Ungar et al., 2001), and the third is the Bacillus halodurans 6 TMS voltage-gated Na+ channel (TC #1.A.1.14.1; Ren et al., 2001). This last-mentioned protein, called NaChBac, is most similar in sequence to voltage-gated Ca2+ channels (TC #1.A.1.11.1-3). A family of these 6 TMS voltage-gated Na+ channels (22-54% identical) is widespread in bacteria, suggesting a fundamental function (Koishi et al., 2004). These three proteins are all distantly related to KcsA of S. lividans, particularly LctB. Kch has been shown to form tetramers that may function to maintain the membrane potential in the early stationary phase of growth (Ungar et al., 2001).

Prokaryotic voltage-gated sodium channels form homotetramers with each subunit contributing six transmembrane α-helices (S1-S6). Helices S5 and S6 form the ion-conducting pore, and helices S1-S4 function as the voltage sensor with helix S4 thought to be the essential element for voltage-dependent activation. The crystal structures have provided insight into voltage-gated K channels, revealing a characteristic domain arrangement in which the voltage sensor domain of one subunit is close to the pore domain of an adjacent subunit in the tetramer. Shimomura et al. (2011) showed that the domain arrangement in NaChBac, (TC# 1.A.1.14.1), is similar to that in voltage-gated K+ channels. The domain arrangement and vertical mobility of helix S4 in NaChBac indicated that the structure and mechanism of voltage-dependent activation in prokaryotic Na+ channels are similar to those in canonical voltage-gated K+ channels (Shimomura et al., 2011).

In eukaryotes, each VIC family channel type has several subtypes based on pharmacological and electrophysiological data. Thus, there are six types of Ca2+ channels (L, N, P, Q, R and T). There are at least ten types of K+ channels, each responding in different ways to different stimuli: voltage-sensitive [Ka, Kv, Kvr, Kvs and Ksr], Ca2+-sensitive [BKCa, IKCa and SKCa] and receptor-coupled [KM and KACh+ channels (I, II, III, μ1, H1 and PN3). Cyclic nucleotide-responsive channels (families 1.A.1.4 and 1.A.1.5) contain centrally located CAP_ED domains, although the cyclic nucleotide regulatory properties have only been reported for family 1.A.5, not 1.A.4. Tetrameric channels from both prokaryotic and eukaryotic organisms are known in which each α-subunit possesses 2 TMSs rather than 6, and these two TMSs are homologous to TMSs 5 and 6 of the 6 TMS unit found in the voltage-sensitive channel proteins. KcsA of S. lividans is an example of such a 2 TMS channel protein. These channels may include the KNa (Na+-activated) and KVol (cell volume-sensitive) K+ channels, as well as distantly related channels such as the Tok1 K+ channel of yeast. The TWIK-1 and -2, TREK-1, TRAAK, and TASK-1 and -2 K+ channels all exhibit a duplicated 2 TMS unit and may therefore form a homodimeric channel. About 50 of these 4 TMS proteins are encoded in the C. elegans genome. Because of insufficient sequence similarity with proteins of the VIC family, inward rectifier K+ IRK channels (ATP-regulated; G-protein-activated) which possess a P domain and two flanking TMSs are placed in a distinct family (TC #1.A.2). However, substantial sequence similarity in the P region suggests that they are homologous. The β, γ, and δ subunits of VIC family members, when present, frequently play regulatory roles in channel activation/deactivation.

The function of voltage-dependent K+ channels is dependent on the negatively charged phosphodiester of phospholipid molecules. A non-voltage-dependent K+ channel does not exhibit the same dependence. It was proposed that the phospholipid membrane, by providing stabilizing interactions between positively charged voltage-sensor arginine residues and negatively charged lipid phosphodiester groups, provides an appropriate environment for the energetic stability and operation of the voltage-sensing machinery. The usage of arginine residues in voltage sensors is an adaptation to the phospholipid composition of cell membranes (Schmidt et al., 2006). The X-ray structure of a voltage-dependent K+ channel (Kv) can explain charge stabilization within the membrane and thus suggests the mechanism for coupling voltage-sensor movements to pore gating (Long et al., 2007).

Voltage-gated ion channels derive their voltage sensitivity from the movement of specific charged residues in response to a change in transmembrane potential. Several studies on mechanisms of voltage sensing in ion channels support the idea that these gating charges move through a well-defined permeation pathway. This gating pathway in a voltage-gated ion channel can also be mutated to transport free cations, including protons (Chanda and Chanda and Bezanilla, 2008). The discovery of proton channels homologous to voltage-sensing domains suggests that the same gating pathway is used by voltage-dependent proton transporters. The voltage sensor depends on the movement of charges in an electric field. Gating currents of the voltage sensor depend on the movements of positively charged arginines through the hydrophobic plug of a voltage sensor domain. Transient movements of these permanently charged arginines, caused by a change in the transmembrane potential further drag the S4 segment and induce opening/closing of the ion conduction pore by moving the S4-S5 linker. Thus, moving permanent charge induces capacitive current flow (Horng et al. 2018).

The voltage-sensing domains (VSDs) of K+ channels have been shown to undergo large rearrangements during gating, whereas the S4 segment may remain positioned between the central pore and the remainder of the VSD in both states (Grabe et al., 2007). In the Shaker K+ channel (1.A.1.2.6), mutation of the first arginine residue of the S4 helix to a smaller uncharged residue makes the VSD permeable to ions in the resting conformation ('S4 down'). There are four omega pores per channel, consistent with one conduction path per VSD. Permeating ions from the extracellular medium enter the VSD at its peripheral junction with the pore domain, and then plunge into the core of the VSD in a curved conduction pathway (Tombola et al. 2007).

Amongst the nine voltage-gated K(+) channel (Kv) subunits expressed in Arabidopsis, AtKC1 does not seem to form functional Kv channels. Co-expression of AtKC1 (1.A.1.4.9), AKT1 (1.A.1.4.1) and/or KAT1 (1.A.1.4.7) genes in tobacco mesophyll protoplasts showed that AtKC1 remains in the endoplasmic reticulum unless it is co-expressed with AKT1 (Duby et al., 2008). Heteromeric AtKC1-AKT1 channels display functional properties different from those of homomeric AKT1 channels. In particular, the activation threshold voltage of the former channels is more negative than that of the latter ones preferred to AKT1-AKT1 homodimers during the process of tetramer assembly. Thus, AtKC1 is a Kv subunit, which downregulates the physiological activity of other Kv channel subunits (Duby et al., 2008).

Shaker-type K+ channels in plants display distinct voltage-sensing properties despite sharing sequence and structural similarity. For example, an Arabidopsis K+ channel (SKOR) and a tomato K+ channel (LKT1) share high amino acid sequence similarity and identical domain structures; however, SKOR conducts outward K+ current and is activated by positive membrane potentials (depolarization), whereas LKT1 conducts inward current and is activated by negative membrane potentials (hyperpolarization). The structural basis for the 'opposite' voltage-sensing properties of SKOR and LKT1 was determined in SKOR channel single amino acid mutations that converted the outward-conducting channel into an inward-conducting channel. Domain-swapping and random mutagenesis produced similar results, suggesting functional interactions between several regions of the SKOR protein that lead to specific voltage-sensing properties. Thus, dramatic changes in rectifying properties can be caused by single amino acid mutations.

The structure of the transmembrane regions of the bacterial cyclic nucleotide-regulated channel MlotiK1 (TC# 1.A.1.25.1), a non-voltage-gated 6 TM channel, has been determined (Clayton et al., 2008). The S1-S4 domain and its associated linker serve as a clamp to constrain the gate of the pore and possibly function in concert with ligand-binding domains to regulate the opening of the pore. Motions of the S6 inner helices can gate the ion conduction pathway at a position along the pore closer to the selectivity filter than the canonical helix bundle crossing.

Carbon monoxide (CO) is a lethal gas, but it is also a physiological signaling molecule capable of regulating a variety of proteins. Among them, large-conductance Ca2+- and voltage-gated K+ (Slo1 BK) channels, important in vasodilation and neuronal firing, have been suggested to be directly stimulated by CO. In fact, CO activates Slo1 BK channels (Hou et al, 2008) in the absence of Ca2+ in a voltage-sensor-independent manner. The stimulatory action of CO requires an aspartic acid and two histidine residues located in the cytoplasmic RCK1 domain. CO probably acts as a partial agonist for the high-affinity divalent cation sensor in the RCK1 domain of the Slo1 BK channel (1.A.1.3.2).

Ca2+-activated BK channels (e.g., 1.A.1.3.3) modulate neuronal activities, including spike frequency adaptation and synaptic transmission. Ca2+-binding sites and the activation gate are spatially separated in the channel protein. By studying an Asp-to-Gly mutation (D434G) associated with human syndrome of generalized epilepsy and paroxysmal dyskinesia (GEPD), Yang et al. (2010) showed that a cytosolic motif immediately following the activation gate S6 helix, known as the AC region, mediates the allosteric coupling between Ca2+ binding and channel opening. The GEPD mutation inside the AC region increases BK channel activity by enhancing this allosteric coupling. Ca2+ sensitivity is enhanced by increases in solution viscosity that reduce protein dynamics. The GEPD mutation alters such a response, suggesting that a less flexible AC region may be more effective in coupling Ca2+ binding to channel opening.

The voltage sensors in VIC family cation channels use a sliding-helix mechanism for electromechanical coupling in which outward movement of gating charges in the S4 transmembrane segments catalyzed by sequential formation of ion pairs pulls the S4-S5 linker, bends the S6 segment, and opens the pore (Catterall, 2010). Impairment of voltage-sensor function by mutations in Na+ channels contributes to several ion channelopathies, and gating pore current conducted by mutant voltage sensors in Na(V)1.4 channels is the primary pathophysiological mechanism in hypokalemic periodic paralysis.

In animals, calcium regulates heartbeat, muscle contraction, neuronal communication, hormone release, cell division, and gene transcription. Major entryways for Ca2+ in excitable cells are high-voltage activated (HVA) Ca2+ channels, Cav (Buraei and Yang, 2010). These are plasma membrane proteins composed of several subunits, including α1, α2δ, β, and γ. Although the principal α1 subunit contains the channel pore, gating machinery and most drug binding sites, the cytosolic auxiliary β subunit plays an essential role in regulating the surface expression and gating properties of HVA Ca2+ channels. Cavβ is also crucial for the modulation of HVA Ca2+ channels by G proteins, kinases, and the Ras-related RGK GTPases. Additional proteins modulate HVA Ca2+ channels by binding to Cavβ, and it may carry out Ca2+ channel-independent functions, including directly regulating gene transcription. All four subtypes of Cavβ, encoded by different genes, have a modular organization, consisting of three variable regions, a conserved guanylate kinase (GK) domain, and a conserved Src-homology 3 (SH3) domain, placing them into the membrane-associated guanylate kinase (MAGUK) protein family. Crystal structures of Cavβs reveal how they interact with Cavα1 (Buraei and Yang, 2010).

Regulator of K+ conductance (RCK) domains control the activity of a variety of K+ transporters and channels, including the human large conductance Ca2+-activated K+ channel that is important for blood pressure regulation and control of neuronal firing, and MthK, a prokaryotic Ca2+-gated K+ channel that has yielded structural insight toward mechanisms of RCK domain-controlled channel gating. In MthK, a gating ring of eight RCK domains regulates channel activation by Ca2+. Pau et al. (2011) showed that each RCK domain contributes to three different regulatory Ca2+-binding sites, two of which are located at the interfaces between adjacent RCK domains. The additional Ca2+-binding sites, resulting in a stoichiometry of 24 Ca2+ions per channel, is consistent with the steep relation between [Ca2+] and MthK channel activity. Comparison of Ca2+-bound and unliganded RCK domains suggests a physical mechanism for Ca2+-dependent conformational changes that underlie gating in this class of channels.

The mechanism of ion channel voltage gating - how channels open and close in response to voltage changes - has been debated since Hodgkin and Huxley's seminal discovery that the crux of nerve conduction is ion flow across cellular membranes. Using all-atom molecular dynamics simulations, Jensen et al. (2012) showed how a voltage-gated potassium channel (KV) switches between activated and deactivated states. On deactivation, pore hydrophobic collapse rapidly halts ion flow. Subsequent voltage-sensing domain (VSD) relaxation, including inward, 15-angstrom S4-helix motion, completes the transition. On activation, outward S4 motion tightens the VSD-pore linker, perturbing linker-S6-helix packing. Fluctuations allow water, then potassium ions, to reenter the pore; linker-S6 repacking stabilizes the open pore. Jensen et al. (2012) proposed a mechanistic model for the sodium/potassium/calcium voltage-gated ion channel superfamily that reconciles apparently conflicting experimental data.

In yeast and filamentous fungi, the Ca2+ channel, Cch1 forms a complex with an auxiliary subunit Mid1 to form the active complex (1.A.1.11.10). Mid1 was originally reported to have Ca2+ channel activity because when produced in Chinese hamster ovary cells, it produced channel activity (Kanzaki et al., 1999). However, it is now clear from many studies that Mid1 is required for Cch1-mediated Ca2+ flux and probably has no inherent channel activity (Ma et al., 2011; Martin et al., 2011; Cavinder and Trail, 2012). Mid1 was originally assigned to TC family: 1.A.16, The Yeast Stretch-Activated Cation-selective Ca2+ Channel, Mid1 (Mid1) Family, but this assignment has been deleted from TCDB, and Mid1 proteins have been incorporated into TC subfamily 1.A.1.11.

Hyperpolarization activated and cyclic nucleotide-gated (HCN) ion channels as well as cyclic nucleotide-gated (CNG) ion channels are essential for the regulation of cardiac cells, neuronal excitability, and signaling in sensory cells (Börger et al. 2014). Both classes are composed of four subunits. Each subunit comprises a transmembrane region, intracellular N- and C-termini, and a C-terminal cyclic nucleotide-binding domain (CNBD). Binding of cyclic nucleotides to the CNBD promotes opening of both CNG and HCN channels. In the case of CNG channels, binding of cyclic nucleotides to the CNBD is sufficient to open the channel. In contrast, HCN channels open upon membrane hyperpolarization and their activity is modulated by binding of cyclic nucleotides, shifting the activation potential to more positive values. Several high-resolution structures of CNBDs from HCN and CNG channels are available.  Börger et al. 2014 reported the complete backbone and side chain resonance assignments of the murine HCN2 CNBD with part of the C-linker.

Plant Shaker channels are members of the 6 transmembrane-1 pore (6TM-1P) cation channel superfamily as are the animal Shaker (Kv) and HCN channels. All these channels are voltage-gated K+ channels: Kv channels are outward-rectifiers, opened at depolarized voltages, and HCN channels are inward-rectifiers, opened by membrane hyperpolarization. Among plant Shaker channels, are outward-rectifiers, inward-rectifiers and weak-rectifiers with weak voltage dependence (Nieves-Cordones and Gaillard 2014). Despite the absence of crystal structures of plant Shaker channels, functional analyses coupled to homology modeling, mostly based on Kv and HCN crystals, have permitted the identification of several regions contributing to plant Shaker channel gating. In a recent mini-review, Nieves-Cordones and Gaillard 2014 updated information on the voltage-gating mechanism of plant Shaker channels which seem to be comparable to that proposed for HCN channels.

The membrane dipole potential (Psid) constitutes one of three electrical potentials generated by cell membranes. Psid arises from the unfavorable parallel alignment of phospholipid and water dipoles, and varies in magnitude both longitudinally and laterally across the bilayer according to membrane composition and phospholipid packing density. Pearlstein et al. 2016 proposed that dynamic counter-balancing between Psid and the transmembrane potential (Δψ) governs the conformational state transitions of voltage-gated ion channels.

In the cell membrane, ion channels and enzymes are able to sense voltage. Sodium, Ca2+ and K+ voltage-dependent channels of the VIC superfamily have a conserved positively charged transmembrane (S4) segment that moves in response to changes in membrane voltage.S4 forms part of a domain that crystallizes as a well-defined structure consisting of the first four transmembrane (S1-S4) segments of the protein, the voltage sensor domain (VSD). VSD movements are allosterically coupled to pore opening to various degrees, depending on the type of channel. How many charges are moved during channel activation, how much they move, and which are the molecular determinants that mediate the electromechanical coupling between the VSD and the pore domains are discussed by Gonzalez et al. 2012.

The family of P-loop channels is characterized by four membrane re-entering extracellular P-loops that connect eight transmembrane helices.  X-ray and cryo-EM structures of the open- and closed-state channels show conserved state-dependent folding despite the fact that the sequences are diverse. In homologous sodium, calcium, TRPV and two-pore channels, the pore-lining helices contain conserved asparagines that may or may not include pi-helix bulges. Comparison of the sequence- and 3D-alignemnts suggests that the asparagines appeared in evolution as insertions that are accommodated in two ways: by pi-helix bulges, which preserve most of inter-segment contacts, or by twists of the C-terminal thirds and switch of inter-segment contacts (Tikhonov and Zhorov 2017). 

Several VIC superfamily K+ channels are affected by molybdenum disulfide nanoflakes (MoS2) (Gu et al. 2017).  For example, MoS2 binds to the extracellular loops of KcsA, which indirectly destroys the delicate structure of the selectivity filter, causing a strong leak of K+ ions.  In the binding mode with Kir3.2, a MoS2 nanoflake completely covers the entrance to the channel pore, affecting ion conduction. For the Kv1.2 chimera, the MoS2 nanoflake prefers to bind into a crevice located at the extracellular side of the Voltage Sensor Domain (VSD). This crevice involves the N-terminal segment of S4, which directly controls the gating process of the Kv1.2 chimera channel by electromechanical coupling of the VSD to the transmembrane electric field (Gu et al. 2017).

Many potassium-channel openers (agonists) share a distinct biaryl-sulfonamide motif. The negatively charged variants of these compounds bind to the top of the voltage-sensor domain, between transmembrane segments 3 and 4, to open the channel. Although biaryl-sulfonamide compounds open some potassium channels, they have also been reported to block sodium and calcium channels (Liin et al. 2018).  The biaryl-sulfonamide motif seems to be a general ion-channel activator motif.

Voltage-dependent activation of voltage-gated cation channels results from the outward movement of arginine-bearing helices within proteinaceous voltage sensors. The arginine side chains in the voltage-sensing residues in potassium channels may make electrostatic or steric contributions to voltage sensing. Infield et al. 2018 functionally characterized engineered Shaker K+ channels, and observed effects on both voltage sensitivity and gating kinetics following substitution of the fourth S4 charged arginine with neutral citrulline, which caused substantial changes in the conductance-voltage relationship and channel kinetics. This suggested that a positive charge is required at this position for efficient voltage sensor deactivation and channel closure.

Toxins of voltage-gated ion channels are broadly divided into two categories—pore blockers that physically occlude the channel pore and gating modifiers that alter channel gating by interfering with the voltage sensor domains (VSDs). Whereas small-molecule neurotoxins such as tetrodotoxin (TTX) and saxitoxin (STX) function as pore blockers, most peptidic Nav channel toxins are gating modifiers that trap the channel in a particular stage of the gating cycle through interactions with one or more VSDs. Shen et al. 2018 determined the structure of NavPaS, the Na+ channel from the American cockroach, bound to a peptide toxin, Dc1a, from the venom of the desert bush spider, Diguetia canitries that specifically binds VSDII of insect Navs to promote chanell opeining, as well as TTX or STX that bind to and block the pore.  Dc1a binds in a cleft between VSDII and hte pore region, causing structural rearrangements (see 8.B.30 for the Dc1a toxin descrption.

Calcium channels play roles in tumorigenesis and progression. although the general underlying mechanisms and the signal transduction pathways are not completely known. Zhong et al. 2019 review the evidence for a linkage between calcium channels and major characteristics of tumors such as multi-drug resistance (MDR), metastasis, apoptosis, proliferation, evasion of immune surveillance, and the alterations of tumor microenvironment. 

Pozdnyakov et al. 2018 characterized the functional determinants (selectivity filter, voltage sensor, Nav-like inactivation gates, Cavbeta-interaction motifs, and calmodulin-binding region)of 277 eukaryotic VIC family members and applied these data to a phylogenetic tree. This allowed them to uncovering of lineage-specific structural gains and losses in the course of evolution and suggest the ancient structural features of these channels.

The generalized transport reaction catalyzed by members of the VIC family is:

cation (out) ⇌ cation (in).



This family belongs to the VIC Superfamily.

 

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Examples:

TC#NameOrganismal TypeExample
1.A.1.1.1

2 TMS K+ and water channel (conducts K+ (KD = 8 mM); blocked by Na+ (190 mM) (Renart et al., 2006) and tetrabutylammonium (Iwamoto et al., 2006)). Ion permeation occurs by ion-ion contacts in single file fashion through the selectivity filter (Köpfer et al. 2014). A narrow pore lined with four arrays of carbonyl groups is responsible for ion selectivity, whereas a conformational change of the four inner transmembrane helices (TMS2) is involved in gating (Baker et al. 2007). Two gates have been identified; one is located at the inner bundle crossing and is activated by H+ while the second gate is in the selectivity filter (Rauh et al. 2017). The C-terminal domain mediates pH modulation (Hirano et al., 2011Pau et al., 2007). KcsA exhibits a global twisting motion upon gating (Shimizu et al., 2008).  Activity is influenced by the phase of the lipid bilayer (Seeger et al. 2010), and occupancy of nonannular lipid binding sites increases the stability of the tetrameric complex (Triano et al. 2010).  The open conformation of KcsA can disturb the bilayer integrity and catalyze the flipping of phospholipids (Nakao et al. 2014).  This protein is identical to the KcsA orthologue (P0A333) in Streptomyces coelicolor.  The stability of the pre domain in KcsA is stabilized by GCN4 (Yuchi et al. 2008).  The potential role of pore hydration in channel gating has been evaluated (Blasic et al. 2015).  Having multiple K+ ions bound simultaneously is required for selective K+ conduction, and a reduction in the number of bound K+ ions destroys the multi-ion selectivity mechanism utilized by K+ channels (Medovoy et al. 2016).  The channel accomodates K+ and H2O molecules alternately in a K+-H2O-K+-H2O  series through the channel (Kratochvil et al. 2016). Insertion of KcsA is spontaneous and directional as the cytosolic part of the protein does not translocate across the membrane barrier. Charged residues, not hydrophobic residues, are crucial for insertion of the unfolded protein into the membrane via electrostatic interactions between membrane and protein.  A two-step mechanism was proposed. An initial electrostatic attraction between membrane and protein represents the first step prior to insertion of hydrophobic residues into the hydrocarbon core of the membrane (Altrichter et al. 2016). Bend, splay, and twist distinguish KcsA gate opening, filter opening, and filter-gate coupling, respectively (Mitchell and Leibler 2017). Details of the water permeability have been presented. Water flow through KcsA is halved by 200 mM K+ in the aqueous solution, which indicates an effective K+ dissociation constant in that range for a singly occupied channel. (Hoomann et al. 2013). A parameterized MARTINI program can be used to predict the hinging motions of the protein (Li et al. 2019).

Gram-positive bacteria

Skc1 (KcsA) of Streptomyces lividans

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.10.1

Voltage-sensitive Na+ channel, NaV1.7 (Cox et al., 2006). The human orthologue, SCN3A when mutated causes cryptogenic pediatric partial epilepsy (Holland et al., 2008). Batrachotoxin (BTX) is a steroidal alkaloid neurotoxin that activates NaV channels through interacting with transmembrane domain-I-segment 6 (IS6) of these channels. Ginsenoside inhibits BTX binding (Lee et al. 2008). VGSCs are heterotrimeric complexes consisting of a single pore-forming alpha subunit joined by two beta subunits, a noncovalently linked beta1 or beta3 and a covalently linked beta2 or beta4 subunit (Hull and Isom 2017).  The binding mode and functional components of the analgesic-antitumour peptide from Buthus martensii Karsch to human voltage-gated sodium channel 1.7 have been characterized (Zhao et al. 2019).

Animals

Voltage-sensitive Na+ channel of Rattus norvegicus

 
1.A.1.10.10

The insect (cockroach) Na+ channel. Batrachotoxin, pyrethroids, and BTG 502 share overlapping binding sites (Du et al., 2011).  Insecticides tagetting Na+ channels include indoxacarb and metaflumizone (Casida and Durkin 2013). They preferably bind to and trap sodium channels in the slow-inactivated non-conducting state, a mode of action similar to that of local anesthetics (Jiang et al. 2015).  Asp802 is involved in gating and action, but not binding, of pyrethroid insecticides (Du et al. 2010).

Animals (Insects)

Na+ channel of Blattella germanica (O01307)

 
1.A.1.10.11

Sodium channel of 2215 aas, VmNa.  An L925V mutation in the channel domain renders the honey bee mites resistant to pyrethroids such as tau- fluvalinate and flumethrin (González-Cabrera et al. 2013).

 

Animals (Insects)

VmNa of Varroa destructor

 
1.A.1.10.12

Type 2 Na+ channel, SCN2A or NaV1.2, of 2,005 aas and 24 TMSs.  Mutations give rise to epileptic encephalophathy, Ohtahara syndrome (Nakamura et al. 2013). They may also give rise to autism (ASD) (Tavassoli et al. 2014). This protein is orthologous to the rat Na+ channel, TC# 1.A.1.10.1 and very similar to the type 1 Na+ channel (1.A.1.10.7). NaV1.2 has a single pore-forming alpha-subunit and two transmembrane beta-subunits. Expressed primarily in the brain, NaV1.2 is critical for initiation and propagation of action potentials. Milliseconds after the pore opens, sodium influx is terminated by inactivation processes mediated by regulatory proteins including calmodulin (CaM). Both calcium-free (apo) CaM and calcium-saturated CaM bind tightly to an IQ motif in the C-terminal tail of the alpha-subunit. Thermodynamic studies and solution structure (2KXW) of a C-domain fragment of apo 13C,15N- CaM (CaMC) bound to an unlabeled peptide with the sequence of the rat NaV1.2 IQ motif showed that apo CaMC (a) was necessary and sufficient for binding, and (b) bound more favorably than calcium-saturated CaMC. CaMN  apparently does not influence apo CaM binding to NaV1.2IQp (Mahling et al. 2017).


Animals

SCN2A of Homo sapiens

 
1.A.1.10.13

Voltage-sensitive Na+ channel of 2821 aas and 24 TMSs (Cohen et al. 2009). Pyrethroid, an insecticide, binds to insect Na+ channels at two sites called pyrethroid,receptors, PyR1 (initial) and PyR2, located in the domain interfaces II/III and I/II, respectively, and binding residues have been identified (Du et al. 2015).

Animals

Na+ channel of Drosophila melanogaster

 
1.A.1.10.14

The voltage-gated Ca2+ channel (VDCC; CAV2), α-subunit of 2027 aas and 24 TMSs in four domains, each with six transmembrane segments and EEEE loci in the ion-selective filter, typical of VDCCs in vertebrates. CAV2 primarily localizes in the distal part of flagella and is transported toward the flagellar tip via intraflagellar transport (IFT) although CAV2 accumulates near the flagellar base when IFT is blocked. Thus, Ca2+ influx into Chlamydomonas flagella is mediated by the VDCC, CAV2, whose distribution is biased to the distal region of the flagellum, and this is required for flagellar waveform conversion (Fujiu et al. 2009).

Plants (Algae)

CAV2 of Chlamydomonas reinhardtii (Chlamydomonas smithii)

 
1.A.1.10.15

The sodium channel of 1989 aas and 24 TMSs.  80% identical to the characterized channel of the crayfish (Astacus leptodactylus (Turkish narrow-clawed crayfish) (Pontastacus leptodactylus)) in which functional regions responsible for the selectivity filter, inactivation gate, voltage sensor, and phosphorylation have been identified (Coskun and Purali 2016).

Na+ channel of Cancer borealis (Jonah crab)

 
1.A.1.10.16

The voltage-gated sodium channel of 2147 aas and 24 TMSs.  Several mutations in the structural gene give rise to pyrethroid resistance (kdr) (Saavedra-Rodriguez et al. 2007).

Na+ channel of Aedes aegypti (Yellowfever mosquito) (Culex aegypti), the most prevalent vector of dengue and yellow fever viruses.

 
1.A.1.10.17

Voltage-gated Na+ Channel protein of 2,139 aas and 24 TMSs.  Mediates voltage-dependent sodium ion permeability of excitable membranes.  3-d modeling revealed spacial clustering of evolutionarily conserved acidic residues at extracellular sites (Vinekar and Sowdhamini 2016).

PARA sodium channel of Anopheles gambiae (African malaria mosquito)

 
1.A.1.10.18

Sodium channel protein, α-subunit, FPC1, of 2050 aas and 24 TMSs.  The 3-d structure has been solved by cryoEM to 3.8 Å resolution (Shen et al. 2017). One residue at the corresponding selectivity filter (SF) locus in each repeat, Asp/Glu/Lys/Ala (DEKA), determines Na+ selectivity. The S1 to S4 segments in each repeat form a voltage-sensing domain (VSD), wherein S4 carries repetitively occurring positive residues essential for voltage sensing. There are seven extracellular glycosylation sites (Shen et al. 2017).

FPC1 of Periplaneta americana (American cockroach) (Blatta americana)

 
1.A.1.10.19

Sodium channel Nav1.4-beta complex of 1820 and 209 aas, respectively.  Voltage-gated sodium (Nav) channels initiate and propagate action potentials. Yan et al. 2017 presented the cryo-EM structure of EeNav1.4, the Nav channel from electric eel, in complex with the beta1 subunit at 4.0 Å resolution. The immunoglobulin domain of beta1 docks onto the extracellular L5I and L6IV loops of EeNav1.4 via extensive polar interactions, and the single transmembrane helix interacts with the third voltage-sensing domain (VSDIII). The VSDs exhibit ""up"" conformations, while the intracellular gate of the pore domain is kept open by a digitonin-like molecule. Structural comparison with closed NavPaS shows that the outward transfer of gating charges is coupled to the iris-like pore domain dilation through intricate force transmissions involving multiple channel segments. The IFM fast inactivation motif on the III-IV linker is plugged into the corner enclosed by the outer S4-S5 and inner S6 segments in repeats III and IV, suggesting a potential allosteric blocking mechanism for fast inactivation (Yan et al. 2017). The PDB# for the complex is 5XSY, and that for the two subunits are 5XSY_A and 5XSY_B. Domain 4 TMS 6 of Nav1.4 plays a key role in channel gating regulation, and is targeted by the neurotoxin, veratridine (VTD) (Niitsu et al. 2018).

Nav1.4-beta subunits of Electrophorus electricus (Electric eel) (Gymnotus electricus)

 
1.A.1.10.2Na+ channel, α-subunit, SCAP1 MetazoaSCAP1 from Aplysia californica (P90670)
 
1.A.1.10.20

Voltage-gated sodium channel of 1836 aas and 24 TMSs, PaFPC1. The 3-d structure has been determined (Shen et al. 2017).  It mediates the voltage-dependent sodium ion permeability in excitable membranes.

t

PaFPC1 of Periplaneta americana (American cockroach) (Blatta americana)

 
1.A.1.10.21

Putative two component voltage-gated Na+ channel, subunit 1 of 1149 aas and subunit 2 of 958 aas.  Decreased expression of these genes, encoding this system, gives rise to mortality of the peach-potato aphid, Myzus persicae (Tariq et al. 2019).

NaV of Myzus persicae.

 
1.A.1.10.3

Ca2+-regulated heart Na+ channel, Nav1.5, SCN5A or INa channel of 2016 aas. The COOH terminus functions in the control of channel inactivation and in pathologies caused by inherited mutations that disrupt it (Glaaser et al., 2006); regulated by ProTx-II Toxin (Smith et al. 2007), telethonin, the titin cap protein (167aas; secreted protein; O15273) (Mazzone et al., 2008), and the Mog1 protein, a central component of the channel complex (Wu et al., 2008). Nav1.5, the principal Na+ channel in the heart, possesses an ankyrin binding site, and direct interaction with ankyrin-G is required for the expression of Nav1.5 at the cardiomyocyte cell surface (Bennett and Healy, 2008; Lowe et al., 2008). Mutations cause type 3 long QT syndrome and type 1 Brugada syndrome, two distinct heritable arrhythmia syndromes (Mazzone et al., 2008; Kapplinger et al. 2010; Wang et al. 2015). SCN5A mutations causing arrhythmic dilated cardiomyopathy, commonly localized to the voltage-sensing mechanism, and giving rise to gating pore currents (currents that go through the voltage sensor) have been identified (McNair et al., 2011; Moreau et al., 2014).  Patients with Brugada syndrome are prone to develop ventricular tachyarrhythmias that may lead to syncope, cardiac arrest or sudden cardiac death (Sheikh and Ranjan 2014) and (Kapplinger et al. 2015). Mutations causing disease have been identified (Qureshi et al. 2015). These give rise to arrhythias and cardiomyopathies (Moreau et al. 2015).  Mutations that cause relative resistance to slow inactivation have been identified (Chancey et al. 2007).  Green tea catechins are potential anti-arrhythmics because of the significant effect of Epigallocatechin-3-Gallate (E3G) on  cardiac sodium channelopathies that display a hyperexcitability phenotype (Boukhabza et al. 2016). A mutatioin, R367G, causes the familial cardiac conductioin disease (Yu et al. 2017). The C-terminal domain of calmodulin (CaM) binds to an IQ motif in the C-terminal tail of the alpha-subunit of all NaV isoforms, and contributes to calcium-dependent pore-gating in some (Isbell et al. 2018). Ventricular fibrillation in patients with Brugada syndrome (BrS) is often initiated by premature ventricular contractions, and the presence of SCN5A mutations increases the risk upon exposure to sodium channel blockers in patients with or without baseline type-1 ECG (Amin et al. 2018). A mutation (R367G) is associated with familial cardiac conduction disease (Yu et al. 2017).

Animals

Nav1.5 of Homo sapiens (Q14524)

 
1.A.1.10.4

The skeletal muscle Na+ channel, NaV1.4 of 1836 aas and 24 TMSs. Mutations in charged residues in the S4 segment cause hypokalemic periodic paralysis (HypoPP)) due to sustained sarcolemmal depolarization (Struyk and Cannon 2007; Sokolov et al., 2007; Groome et al. 2014). Also causes myotonia; regulated by calmodulin which binds to the C-terminus of Nav1.4 (Biswas et al., 2008). NaV1.4 gating pores are permeable to guanidine as well as Na+ and H+ (Sokolov et al., 2010). The R669H mutation allows transmembrane permeation of protons, but not larger cations, similar to the conductance displayed by histidine substitution at Shaker K+ channel S4 sites (Struyk and Cannon 2007).  The mechanism of inactivation involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the beta1 subunit (Sánchez-Solano et al. 2016). Potassium-sensitive hypokalaemic and normokalaemic periodic paralysis are inherited skeletal muscle diseases in humans, characterized by episodes of flaccid muscle weakness. They are caused by single mutations in positively charged residues ('gating charges') in the S4 transmembrane segment of the voltage sensor of the voltage-gated sodium channel Nav1.4 or the calcium channel Cav1.1. Mutations of the outermost gating charges (R1 and R2) cause hypokalaemic periodic paralysis by creating a pathogenic gating pore in the voltage sensor through which cations leak in the resting state. Mutations of the third gating charge (R3) cause normokalaemic periodic paralysis owing to cation leak in both activated and inactivated states (Jiang et al. 2018). The neurotoxic cone snail peptide μ-GIIIA specifically blocks skeletal muscle voltage-gated sodium (NaV1.4) channels (Leipold et al. 2017). the cryo-electron microscopy structure of the human Nav1.4-β1 complex at 3.2-Å resolution. Accurate model building was made for the pore domain, the voltage-sensing domains, and the β1 subunit (Pan et al. 2018) provided insight into the molecular basis for Na+ permeation and kinetic asymmetry of the four repeats. Structural analysis of reported functional residues and disease mutations corroborates an allosteric blocking mechanism for fast inactivation of Nav channels.

 

Animals

NaV1.4 of Homo sapiens (P35499)

 
1.A.1.10.5

Voltage-sensitive Na channel, type 9, α-subunit, Nav1.7 or SCN9A (orthologous to 1.A.1.10.1). Loss of function, resulting from point mutations, results in a channelopathy called Congenital Insensitivity to Pain (CIP) (He et al. 2018), that causes the congenital inability to experience pain (Cregg et al., 2010; Kleopa, 2011). An S241T mutation causes inherited erythromelalgia IEM; erythermalgia, an autosomal dominant neuropathy characterized by burning pain in the extremities in response to mild warmth (due to altered gating) (Lampert et al., 2006; Drenth and Waxman, 2007). Gain-of-function mutations in the Na(v)1.7 channel lead to DRG neuron hyperexcitability associated with severe pain, whereas loss of the Na(v)1.7 channel in patients leads to indifference to pain (Dib-Hajj et al., 2007). Blocked by 1-benzazepin-2-one (Kd = 1.6 nM) (Williams et al., 2007). Mutations in the Nav1.7 Na channel α-subunit give rise to familial pain syndromes called chronic non-paoxysmal neuropathic pain (Catterall et al., 2008; Fischer and Waxman, 2010; Dabby et al. 2011 ). It interacts with the sodium channel beta3 (Scn3b), rather than the beta1 subunit, as well as the collapsing-response mediator protein (Crmp2) through which the analgesic drug lacosamide regulates Nav1.7 current (Kanellopoulos et al. 2018). The R1488 variant is totally inactive (He et al. 2018). Nav1.7 is inhibited by knottins (see TC# 8.B.19.2) (Agwa et al. 2018). Nav1.7 interacts with the following proteins: syn3b (TC# 8.a.17.1.2; the β3 subunit), Crmp2, Syt2 (Q8N9I0) and Tmed10 (P49755), and it also regulates opioid receptor efficacy (Kanellopoulos et al. 2018). Mutations in TRPA1 and Nav1.7 to  insensitivity to pain-promoting algogens such as capsaicin, acid, and allyl isothiocyanate (AITC), have been documented (Eigenbrod et al. 2019).

Animals

Nav1.7 of Homo sapiens (Q15858)

 
1.A.1.10.6

Tetrodotoxin-resistant voltage-gated Na+ channel of dorsal ganglion sensory neurons, Nav1.8 (Akopian et al., 1996). Essential for pain at low temperatures (Zimmermann et al., 2007). Nav1.8 is the sole electrical impulse generator in a nociceptor that transmits information to the central nervous system.  Bark scorpion venom induces pain in many mammals (house mice, rats, humans) by activating Nav1.7 but has no effect on Nav1.8. Grasshopper mice Nav1.8 has amino acid variants that bind bark scorpion toxins and inhibit Na+ currents, blocking action potential propagation and inducing analgesia.  These mice thereby can use scorpions as a food source (Zhu et al. 2013; Rowe et al. 2013). Nav1.8 is involved in bull spermatozoa dynamics including motility, membrane integrity, acrosome integrity, capacitation and mitochondrial transmembrane potential (Chauhan et al. 2017).

Animals

Nav1.8 of Rattus norvegicus
(Q62968)

 
1.A.1.10.7

Voltage-sensitive Na+ channel, Nav1.1 or SCN1A (causes epilepsy when mutated) (Rusconi et al., 2007).  Mutations are associated with a wide range of mild to severe epileptic syndromes with phenotypes ranging from the relatively mild generalized epilepsy with febrile seizures to other severe epileptic encephalopathies (Colosimo et al. 2007), including myoclonic epilepsy in infancy (SMEI), cryptogenic focal epilepsy (CFE), cryptogenic generalized epilepsy (CGE) and a distinctive subgroup termed as severe infantile multifocal epilepsy (SIMFE) (Ben Mahmoud et al. 2015). Mutations can give rise to familial sporadic hemiplegic migranes (Prontera et al. 2018).

Animals

Nav1.1 of Homo sapiens (P35498)

 
1.A.1.10.8

The Voltage-gated Na+ channel α-subunit, Nav1.6, encoded by the Scn8a gene which when defective gives rise to the ENU-induced neurological mutant ataxia3 which gives rise to ataxia, tremors, and juvenile lethality.   75% identical to 1.A.1.10.7. Nav1.6 is the dendritic, voltage-gated sodium channel (responsible for dendritic excitability (Lorincz and Nusser, 2010)). Nav1.6 (SCN8A) interacts with microtubule-associated protein (O'Brien et al., 2012). Scorpion alpha toxins bind at receptor site-3 and inhibit channel inactivation, whereas beta toxins bind at receptor site-4 and shift the voltage-dependent activation toward more hyperpolarizing potentials (Gurevitz, 2012).  Mutations give rise to epileptic encephalopathy and intellectual disability (O'Brien and Meisler 2013).  A gain-of-function mutation gave rise to increased channel activation and infantile epileptic encephalopathy (Estacion et al. 2014). Benign familial infantile seizures (BFIS), paroxysmal kinesigenic dyskinesia (PKD), and their combination - known as infantile convulsions and paroxysmal choreoathetosis (ICCA) - are related autosomal dominant diseases involving SCN8A (Gardella et al. 2015).  Mutations can lead to chronic movement disorder in the mouse (Jones et al. 2016), and loss of function mutations in humans can lead to intellectual disability without seizures (Wagnon et al. 2017). Nav1.6 has been quantitated in mouse brain and proved to be present in 2-fold decreased amounts in epileptic mice (Sojo et al. 2019).

Animals

Nav1.6 of Homo sapiens (Q9UQD0)

 
1.A.1.10.9

The voltage-gated Na+ channel α-subunit, Nav1.9. It is present in excitable membranes and is resistant to tetrodotoxin and saxitoxin (Bosmans et al., 2011).  The mutation, S360Y, makes NaV1.9 channels sensitive to tetrodotoxin and saxitoxin, and the unusual slow open-state inactivation of NaV1.9 is mediated by the isoleucine-phenylalanine-methionine inactivation motif located in the linker connecting domains III and IV (Goral et al. 2015).  Gain-of function mutations can lead to heritable pain disorders, and painful small-fibre neuropathy (Han et al. 2016). It is a threshold channel that regulates action potential firing, and is preferentially expressed in myenteric neurons, the small-diameter dorsal root ganglion (DRG) and trigeminal ganglion neurons including nociceptors. There is a monogenic Mendelian link of Nav1.9 to human pain disorders including episodic pain due to a N816K mutation (Huang et al. 2019).

.

 

Animals

Nav1.9 of Homo sapiens (Q9UI33)

 
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample
1.A.1.11.1Voltage-sensitive Ca2+ channel (transports Ca2+, Ba2+ and Sr2+) Animals Voltage-sensitive Ca2+ channel, α-1 chain of Rattus norvegicus
 
1.A.1.11.10

Plasma membrane voltage-gated, high affinity Ca2+ channel, Cch1/Mid1; activated by mating pheromones and environmental stresses; required for growth in low Ca2+ (Locke et al., 2000; Paidhungat and Garrett, 1997). Also essential for tolerance to cold stress and iron toxicity (Peiter et al., 2005). Ecm7, (448aas; 4 TMS; TC# 1.H.1.4.6), a member of the PMP-22/EMP/MP20 Claudin superfamily of transmembrane proteins that includes gamma-subunits of voltage-gated calcium channels appears to interact with Mid1 TC# 8.A.41.1.1) and regulate the activity of the Cch1/Mid1 channel (Martin et al., 2011). Ecm7p is related to members of TC families 1.H.1, 1.H.2 and 1.A.81. The two indispensable subunits, Cch1 and Mid1 are equivalent to the mammalian pore-forming α1 and auxiliary α2 /δ subunits, respectively. Cho et al. 2016 screened candidate proteins that interact with Mid1 and identified the plasma membrane H+-ATPase, Pma1 (TC#3.A.3.3.6). Mid1 co-immunoprecipitated with Pma1. At the nonpermiss, and Mid1-EGFP colocalized with Pma1-mCherry at the plasma membrane.  Using a temperature-sensitive mutant, pma1-10, the membrane potential was less negative, and Ca2+ uptake was lower than in wild-type cells. Thus, Pma1 interacts physically with Cch1/Mid1 Ca2+ channels to enhance their activity via its H+-pumping activity (Cho et al. 2016).

Yeast

Cch1/Mid1 of Saccharomyces cerevisiae
Cch1 (P50077)
Mid1 (P41821)
Ecm7p (Q06200) 

 
1.A.1.11.11

The Cav1.4 Ca2+ channel (gene CACNA1F). Mutations resulting in increased activity cause x-linked incomplete congenital stationary night blindness (CSNB2) (Hemara-Wahanui et al., 2005; Peloquin et al., 2007).  Aland Island eye disease (AIED), also known as Forsius-Eriksson syndrome, is an X-linked recessive retinal disease characterized by a combination of fundus hypopigmentation, decreased visual acuity, nystagmus, astigmatism, protan color vision defect, progressive myopia, and defective dark adaptation. Since the clinical picture of AIED is quite similar to CSNB2, these disorders are allelic or form a single entity. Thus, AIED is also caused by CACNA1F gene mutations (Jalkanen et al. 2007).

Animals

Cav1.4 of Homo sapiens
(O60840)

 
1.A.1.11.12

T-type Ca2+ channel (CACNA1G; Cav3.1d), (σ1G T-type Ca2+ channel) in developing heart (fetal myocardium (Cribbs et al., 2001)) and elsewhere. Both Cav3.1 and Cav3.2 are permeated by divalent metal ions, such as Fe2+ and Mn2+, and possibly Cd2+ (Thévenod, 2010).  CaV3.1 channels are activated at low votage and regulate neuronal excitability in the spinal cord (Canto-Bustos et al. 2014).  It is regulated by protein kinase C (PKC) and the RanBPM protein (Q96S59) (Kim et al. 2009).  T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channel is an opening at quite negative potentials and voltage-dependent inactivation. T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells, and support calcium signaling in secretory cells and vascular smooth muscle (Coutelier et al. 2015). The human ortholog is 85% identical to the mouse protein. These channels also determines the angiogenic potential of pulmonary microvascular endothelial cells (Zheng et al. 2019).

 

Animals

Cav3.1d of Mus musculus (Q9WUT2)

 
1.A.1.11.13Two-pore Ca2+ channel protein 1, TPC1 (Km(Ca2+))=50 µM; voltage gated; 461 aas; 6TMSs) (Hashimoto et al., 2004; Kurusu et al, 2004; 2005)Plants TPC1 of Oryza sativa (Q5QM84)
 
1.A.1.11.14Voltage-dependent calcium channel, α-1 subunit (1911aas), CyCaα1AnimalsCyCaα1 of Cyanea capillata (O02038)
 
1.A.1.11.15

Neuronal nonselective cation channel, NALCN (forms background leak conductance and controls neuronal excitability; Lu et al., 2007).  It is also found in the pancreatic β-cell (Swayne et al. 2010). NALCN serves as a variable sensor that responds to calcium or sodium ion flux, depending on whether the total cellular current density is generated more from calcium-selective or sodium-selective channels (Senatore and Spafford 2013). It functions in a complex with Unc80 (3258 aas; Q8N2C7) and Unc79 (2635 aas; Q9P2D8) (Bramswig et al. 2018). Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (Bramswig et al. 2018). Overexpression of the NALCN gene ablates allyl isothiocyanate-promoting pain reception by nociceptors (Eigenbrod et al. 2019).

Animals

NALCN of Homo sapiens (Q6P2S6)

 
1.A.1.11.164 domain-type voltage-gated ion channel, α-1 subunit NCA-2 (Jospin et al., 2007) (dependent on Unc-80 (3225aas; CAB042172) for proper localization).AnimalsNCA-2 of Caenorhabditis elegans (Q06AY4)
 
1.A.1.11.17

The high affinity Ca2+ channel; associates with elongation factor 3 (EF3) to target Cch1/Mid1 to the plasma membrane (Liu and Gelli, 2008).

Fungi

Cch1/Mid1 of Cryptococcus neoformans
Cch1 (Q1HHN2)
Mid1 (Q5KM96) 

 
1.A.1.11.18

The nicotinic acid adenine dinucleotide phosphate (NAADP)- dependent two pore Ca2+- channel, TPC3 (Brailoiu et al., 2010).

Animals

Two pore Ca2+ channel 3, TPC3 of Bos taurus (C4IXV8)

 
1.A.1.11.19

The phosphoinositide (PI(3,5)P2)-activated Na+ two pore channel-2, TPC2, in endosomes and lysosomes (Wang et al. 2012). Previously thought, incorectly, according to Wang et al. 2012, to be a nicotinic acid adenine dinucleotide phosphate (NAADP)-dependent two pore Ca2+ channel.  TPC2, like TPC1, has a 12 TMS topology (two channel units) (Hooper et al., 2011). The two domains of human TPCs can insert into the membrane independently (Churamani et al., 2012).  Cang et al. (2013), showed that TPC1 and TPC2 together form an ATP-sensitive two-pore Na+ channel that senses the metabolic state of the cell.  The channel complex detects nutrient status, becomes constitutively open upon nutrient removal, and controls the lysosome's membrane potential, pH stability, and amino acid homeostasis.  Essential for Ebola virus (EBOV) host entry. Several inhibitors of TPC2 that act in the nM (tetrandrine) or μM (verapamil; Ned19) range block channel activity, prevent Ebola Virus from escaping cell vesicles and may be used to treat the disease (Sakurai et al. 2015).  TPC2 may transport both Na+ and Ca2+ (Sakurai et al. 2015).

Animals

TPC2 of Homo sapiens (Q8NHX9)

 
1.A.1.11.2

Muscle plasmalemma, voltage-gated, L-type dihydropyridine receptor Ca2+ channel, α-1 subunit (DHPR) (Ba2+ > Ca2+), Cav1.1, CACNA1S,CACH1 CDCN1, CACNL1A3 of 1873 aas in the human orthologue.  Distinc voltage sensor domains control voltage sensitivity and kinetics of current activation (Tuluc et al. 2016).

Animals

DHPR of Oryctolagus cuniculus

 
1.A.1.11.20

The voltage-gated Ca2+ channel, L-type α-subunit, Eg1-19 regulated by Macoilin (8.A.38.1.2)

Animals

Eg1-19 of Caenorhabditis elegans (A8PYS5)

 
1.A.1.11.21

Voltage-gated Ca2+ channel, Egl-19, isoform a

Animals

Egl-19 of C. elegans (G5EG02)

 
1.A.1.11.22

The phosphoinositide (PI(3,5)P2)-activated Na+ two pore channel-1, TPC1 of endosomes and lysosomes (Wang et al. 2012). Previously thought, incorectly, according to Wang et al. (2012), to be an NAADP-activated two pore voltage-dependent calcium channel protein.  However, Cang et al. (2013), showed that TPC1 and TPC2 (TC# 1.A.1.11.19) together form an ATP-sensitive two-pore Na+ channel that senses the metabolic state of the cell.  The channel complex detects nutrient status, becomes constitutively open upon nutrient removal, and controls the lysosome's membrane potential, pH stability, and amino acid homeostasis.  May be regulated by the HCLS-associated X-1 (HAX-1) protein (Lam et al. 2013). The cryoEM 3-D structure has been ellucidated (She et al. 2018). This voltage-dependent, phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2)-activated Na+ channel was solved in both the apo closed state and ligand-bound open state. The channel has a coin-slot-shaped ion pathway in the filter that defines the selectivity of mammalian TPCs. Only the voltage-sensing domain from the second 6-TMS domain confers voltage dependence while endolysosome-specific PtdIns(3,5)P2 binds to the first 6-TMS domain and activates the channel under conditions of depolarizing membrane potential. Structural comparisons between the apo and PtdIns(3,5)P2-bound structures show the interplay between voltage and ligand activation. These MmTPC1 structures reveal lipid binding and regulation in a 6-TMS voltage-gated channel (She et al. 2018).

Animals

Tpcn1 of Mus musculus

 
1.A.1.11.23

Cch1 calcium channel, alpha subunit; acts with Mid1 (8.A.41.1.7) which is required for function.

Fungi

Mid1 of Schizosaccharomyces pombe

 
1.A.1.11.24

Voltage-sensitive calcium channel of 2693 aas (Docampo et al. 2013). Found to be essential for bloodstream-form Trypanosoma brucei through a genome-wide RNAi screen (Schmidt et al. 2018).

Euglenozoa (Protozoa)

Calcium channel of Trypanosoma brucei

 
1.A.1.11.25

Endosomal/lysosomal, two pore Na+and Ca2+-release channel  (Na+> Ca2+) protein of 816 aas and 12 TMSs, TPC1 or TPCN1 (Guo et al. 2017).  Endosomes and lysosomes are electrically excitable organelles (Cang et al. 2014). In a subpopulation of endolysosomes, a brief electrical stimulus elicits a prolonged membrane potential depolarization spike. The organelles have a depolarization-activated, non-inactivating Na+ channel (lysoNaV). The channel is formed by a two-repeat six-transmembrane-spanning (2x6 TMS) protein, TPC1, which represents the evolutionary transition between 6 TMS and 4x6 TMS voltage-gated channels. Luminal alkalization also opens lysoNaV by markedly shifting the channel's voltage dependence of activation toward hyperpolarization. Thus, TPC1 is a voltage-gated Na+ channel that senses pH changes and confers electrical excitability to organelles (Cang et al. 2014). Essential for Ebola virus (EBOV) host entry.  Several inhibitors act in the nM (tetrandrine) or μM (verapamil; Ned19) range to block Na+ and Ca2+ channel activity, inhibit virus escape from membrane vesicles and may possibly be used to treat the disease (Sakurai et al. 2015). A cluster of arginine residues in the first domain required for selective voltage-gating of TPC1 map not to the voltage-sensing fourth transmembrane region (S4) but to a cytosolic downstream region (S4-S5 linker). These residues are conserved between TPC isoforms suggesting a generic role in TPC activation. Accordingly, mutation of residues in TPC1 but not the analogous region in the second domain prevents Ca2+ release by NAADP in intact cells (Patel et al. 2017). Dramatic conformational changes in the cytoplasmic domains communicate directly with the VSD during activation (Kintzer et al. 2018).

Animals

TPC1 of Homo sapiens

 
1.A.1.11.26

Two pore Ca2+ > Na+, Li+ or K+ (non-selective for these three monovalen caions) channel protein of 733 aas and 12 TMSs, TPC1 (Guo et al. 2017). The crystal structure of this vacuolar two-pore channel, a homodimer, has been solved (Guo et al. 2015) (Kintzer and Stroud 2016). Activation requires both voltage and cytosolic Ca2+. Ca2+ binding to the cytosolic EF-hand domain triggers conformational changes coupled to the pair of pore-lining inner helices from the first 6-TMS domains, whereas membrane potential only activates the second voltage-sensing domain, the conformational changes of which are coupled to the pair of inner helices from the second 6-TMS domains. Luminal Ca2+ or Ba2+ modulates voltage activation by stabilizing the second voltage-sensing domain in the resting state and shift voltage activation towards more positive potentials. The basis for understanding ion permeation, channel activation, the location of voltage-sensing domains and regulatory ion-binding sites is partially explained by the 3-d structure (Kintzer and Stroud 2016). Only the second Shaker domain senses voltage (Jaślan et al. 2016). It has a selectivity filter that is passable by hydrated divalent cations (Demidchik et al. 2018).

Plants

TPC1 of Arabidopsis thaliana

 
1.A.1.11.27

Voltage-dependent P/Q-type Ca2+ channel subunit α1A, CACNA1A (CACH4; CACN3; CACNL1A4) of 2,505 aas.  90% identical to 1.A.1.11.8.  Associated with four neurological phenotypes: familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6) and epileptic encephalopathu with nerve atrophy (Reinson et al. 2016). A gain of function mutation gave symptoms of congenital ataxia, abnormal eye movements and developmental delay with severe attacks of hemiplegic migraine (García Segarra et al. 2014). Mutations can cause F/SHM with high penitrance (Prontera et al. 2018).

Animals

CACNA1A Ca2+ channel of Homo sapiens

 
1.A.1.11.28

Voltage-dependent L-type calcium channel subunit α, VDCC, CCA-1 or CaACNa1S, of 1873 aas and 24 TMSs. Ca2+ channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle.  They are regulated by dystrophin-1 (Zhan et al. 2014).

VDCC of Caenorhabditis elegans

 
1.A.1.11.29

Voltage-gated calcium channel (VDCC) of 3097 aas and 24 TMSs, Cav7 (Wheeler and Brownlee 2008). 

Cav7 of Chlamydomonas reinhardtii

 
1.A.1.11.3

Voltage-dependent R-type Ca2+ channel, α-1E subunit (Cav2.3) (brain Ca2+ channel type II) (Ca2+ > Ba2+). Interacts with V-type ATPases (3.A.2), specifically, the G1-subunit, to regulate its activity (Radhakrishnan et al., 2011).  Syntaxin-3 (Syn-3) interacts directly with Cav2.3 to regulate its activity (Xie et al. 2016).

Animals

R-type Ca2+ channel of Mus musculus

 
1.A.1.11.30

TPC calcium channel protein with two transmembrane domains of 6 TMSs each (720 aas and 12 TMSs) (Wheeler and Brownlee 2008).

TPC of Physcomitrella patens

 
1.A.1.11.31

Voltage-sensitive calcium channel (VSCC), CAV1.3, of 2161 aas and 24 TMSs (Singh et al. 2008). CaV1.3-R990H channels conduct omega-currents at hyperpolarizing potentials, but not upon membrane depolarization compared with wild-type channels (Monteleone et al. 2017).

CAv1.3 of Homo sapiens

 
1.A.1.11.32

Pore-forming, alpha-1S subunit of the voltage-gated calcium channel of 1873 aas and 24 TMSs, Cav1.1; CACNA1S; CACN1; CACH1; CACNL1A3, that gives rise to L-type calcium currents in skeletal muscle. Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle via their interaction with RYR1, which triggers Ca2+ release from the sarcplasmic reticulum and ultimately results in muscle contraction. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group (Jiang et al. 2018). The 3-d structure of a bacterial homologue has been solved (Jiang et al. 2018).

Cav1.1 of Homo sapiens

 
1.A.1.11.33

Calcium channel protein of 2556 aas and 24 TMSs.  Inhibited by 1,4-dihydrophyridines such as nifedipine (Tempone et al. 2009).

Ca2+ channel of Leishmania donovani

 
1.A.1.11.34

Calcium channel of 913 aas and 12 TMSs. Ca2+ channels in trophozoites are inhibited by Amlodipine (Baig et al. 2013).

Calcium channel of Acanthamoeba castellanii

 
1.A.1.11.35

Calcium channel of 2725 aas and 24 TMSs.  T. cruzi calcium channels are inhibited by fendiline and bepridil (Reimão et al. 2011).

Ca2+ channel of Trypanosoma cruzi

 
1.A.1.11.4

The voltage-dependent L-type Ca2+ channel α-subunit-1C (L-type Cav1.2), CACNA1C (CACH2, CACN2, CACNL1A1, CCHL1A1) of 2221 aa. Mutations cause Timothy's syndrome, a disorder associated with autism (Splawski et al., 2006). The C-terminus of Cav1.2 encodes a transcription factor (Gomez-Ospina et al., 2006). Cav1.2 associates with the α-2, δ-1, β and γ subunits (Yang et al., 2011). The CRAC channel activator STIM1 binds and inhibits L-type voltage-gated calcium channel, Cav1.2 (Park et al., 2010).  This channel appears to function as the molecular switch for synaptic transmission (Atlas 2013). Intramembrane signalling occurs with syntaxin 1A for catecholamine release in chromaffin cells (Bachnoff et al. 2013).  miR-153 intron RNA is a negative regulator of both insulin and dopamine secretion through its effect on Cacna1c expression, suggesting that IA-2beta and miR-153 have opposite functional effects on the secretory pathway (Xu et al. 2015).   Co-localizes with Syntaxin-1A in nano clusters at the plasma membrane (Sajman et al. 2017). It is a high voltage-activated Ca2+ channel in contrast to Cav3.3 which is a low voltage-activated Ca2+ channel (Sanchez-Sandoval et al. 2018). Nifedipine blocks and potentiates this and other L-type VIC Ca2+ channels (Wang et al. 2018).

Animals

CACNA1C of Homo sapiens (2221 aas; Q13936)

 
1.A.1.11.5

The voltage-dependent L-type Ca2+ channel α-subunit-1H (T-type Cav3.2), CACNA1H (mutations can cause an increased propensity for autism spectrum disorders (ASD) characterized by impaired social interactions, communication skills and restricted and repetitive behaviors) (Splawski et al., 2006). Also called Cav3.2 or VSCC. Involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1H gives rise to T-type calcium currents, ''low-voltage activated'' currents blocked by nickel and mibefradil. Defective in Childhood Absence Epilepsy. Are permeated by divalent metal ions, such as Fe2+ and Mn2+ , and possibly Cd2+ (Thévenod, 2010).  Patented inhibitors of T-type calcium channels have been reviewed (Giordanetto et al. 2011).  Regulated by Syntaxin-1A (Xie et al. 2016).

Animals

CACNA1H of Homo sapiens (2353 aas; Q95180)

 
1.A.1.11.6

Voltage-dependent L-type Ca2+ channel subunit α-1C (αCav1.2) of cardiac muscle [A C-terminal fragment of Cav1.2 translocates to the nucleus and regulates transcription, explaining how a channel can directly activate transcription and differentiation of excitable cells.] (Gomez-Ospina et al., 2006). Cav1.2 associates with the α-2, δ-1, β and γ subunits (Yang et al., 2011).

Animals

α-Cav1.2 of Mus muscultus (2139 aas; Q01815)

 
1.A.1.11.7

The voltage-dependent Ca2+ channel subunit α-1I, Cav3.3, CACNA1I (isoform CRA_c (2223 aas and 24 TMSs)) (Hamid et al. 2006). It is a low voltage-activated Ca2+ channel in contrast to Cav1.2 (TC# 1.A.1.11.4) which is a high voltage-activated Ca2+ channel (Sanchez-Sandoval et al. 2018).

Animals

Ca2+ channel CRA_c of Homo sapiens (Q9P0X4)

 
1.A.1.11.8

Voltage-dependent Ca2+ channel α-1A subunit (2212 aas), Cav2.1 (P/Q-type) (when mutated in humans, leads to a human channelopathy (episodic ataxia type-2 (EA2)) due to protein misfolding and retention in the E.R. (Mezghrani et al., 2008; Kleopa, 2011).  Mutations give rise to familial and sporadic hemiplegic migraine type 1 (FHM1, SHM1), episodic ataxia type 2 (EA2), and spinocerebellar ataxia type 6 (SCA6) (García Segarra et al. 2014).  Syntaxin 1A (Sx1A), SNAP-25 and synaptotagmin (Syt1), either alone or in combination, modify the kinetic properties of voltage-gated Ca2+ channels (VGCCs) including Cav2.1 (Cohen-Kutner et al. 2010).

Animals

Cav2.1 of Rattus norvegicus (P54282)

 
1.A.1.11.9

Voltage-dependent Ca2+ channel -subunit 1B (2339 aas), Cav2.2 (N-type) or NCC receptor of 2237 aas. Anchorin B interacts with Cav2.2 in the loop between TMSs 2 and 3.  TSPAN-13 specifically interacts with the α-subunit and modulates the efficiency of coupling between voltage sensor activation and pore opening of the channel while accelerating the voltage-dependent activation and inactivation of the Ba2+ current through CaV2.2 (Mallmann et al. 2013). The structure of the closed state in the pore forming domains have been modeled (Pandey et al. 2012). Amlodipine, cilnidipine and nifedipine compounds are potent channel antagonists.  CaV2.2 also interacts with reticulon 1 (RTN1) (TC# 8.A.102), member 1 of solute carrier family 38 (SLC38, TC#2.A.18), prostaglandin D2 synthase (PTGDS) and transmembrane protein 223 (TMEM223; TC#8.A.115). Of these, TMEM223 and, to a lesser extent, PTGDS, negatively modulate Ca2+ entry, required for transmitter release and/or for dendritic plasticity under physiological conditions (Mallmann et al. 2019).

Animals

Cav2.2 of Mus musculus (O55017)

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.12.1

Paramecium bursaria Chlorella virus 1 (PBCV-1) K+ channel, Kcv1. (The viral-encoded K+ channel inserts into the green algal host membrane to aid ejection of DNA from the viral particle into the cytoplasm (Neupartl et al., 2007)). It may mediate host cell membrane depolarization and K+ loss (Agarkova et al., 2008; Balss et al., 2008).  It is inhibited by Ba2+ and amantidine. (Reviewed by Thiel et al., 2010). The presence of charged amino acids which form dynamic inter- and intra- subunit salt bridges is crucial for channel activity (Hertel et al. 2010).

Virus

Kcv1 K+ channel of Chlorella virus PBCV-1

 
1.A.1.12.2

Acanthocystis turfacea chlorella virus cation, K+-preferring, channel, ATCV1 (82aas) (Gazzarrini et al., 2009; Siotto et al. 2014). The difference in open probability between close isoforms is caused by one long closed state in KcvS versus KcvNTS. This state is structurally created in the tetrameric channel by a transient, Ser mediated, intrahelical hydrogen bond. The resulting kink in the inner transmembrane domain swings the aromatic rings from downstream Phenylalanines in the cavity of the channel, which blocks ion flux.

Algal virus

ATCV1 (KCVS/KCVNTS) of Acanthocystis turfacea chlorella virus (A7K9J5)

 
1.A.1.12.3

The viral K+ channel, Kesv of 124 aas.  It is inhibited by Ba2+ and amantidine.  It is important for infection and replication in marine brown algae (Chen et al. 2005; Balss et al., 2008; Siotto et al. 2014).

Phaeovirus

Kesv of Ectocarpus siliculosus virus 1 (Q8QN67)

 
1.A.1.12.4

Viral K+ channel of 96 aas and 2 TMSs, Kcv (Siotto et al. 2014).  Mechanical perturbation of the N-terminus can be transmitted to the C-terminal channel gates (Hoffgaard et al. 2015).

Viruses

Kcv of Paramecium bursaria Chlorella virus

 
1.A.1.12.5

Potassium ion channel protein of 86 aas and 2 TMSs (Greiner et al. 2018).

K+ channel protein of Micromonas pusilla virus SP1

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.13.1

6TMS K+ channel (Munsey et al. 2002; Kuo et al., 2003).  The kch gene, the only known potassium channel gene in E. coli, has the property to express both full-length Kch and its cytosolic domain (RCK) due to a methionine at position 240. The RCK domains form an octameric ring structure and regulate the gating of the potassium channels after having bound certain ligands. Several different gating ring structures have been reported for the soluble RCK domains.  The octameric structure of Kch may be composed of two tetrameric full-length proteins through RCK interaction (Kuang et al. 2013).  The RCK domains face the solution, and an RCK octameric gating ring arrangement does not form under certain conditions (Kuang et al. 2015).

Gram-negative bacteria

Kch of E. coli

 
1.A.1.13.2

2 TMS ( P-loop) Ca2+-gated K+ channel, MthK (see Jiang et al., 2002 for the crystal structure, and Parfenova et al., 2006 for mutations affecting open probability). For the studies of ion permeation and Ca2+ blockage, see Derebe et al., 2011. (structures: 3LDD_A and 2OGU_A.). Voltage-dependent K+ channels including MthK which lacks a canonical voltage sensor can undergo a gating process known as C-type inactivation, which involves entry into a nonconducting state through conformational changes near the channel's selectivity filter (Thomson and Rothberg, 2010). C-type inactivation may involve movements of transmembrane voltage sensor domains.

 

Euryarchaea

MthK of Methanothermobacter thermoautotrophicus (O27564)

 
1.A.1.13.3Divalent cation (Ca2+, Mg2+, Mn2+, Ni2+)-activated K+ channel, TuoK (contains a RCK domain) (Parfenova et al., 2007)

Archaea

TuoK of Thermoplasma volcanium (Q979Z2)

 

 
1.A.1.13.4

The Biofilm-inducing putative K+ channel, BikC or YugO (Prindle et al. 2015). BikC has an N-terminal 2 TMS + P-loop channel domain and a C-terminal NADB_Rossman superfamily domain (TrkA domain). YugO is in a two cistronic operon where Mistic (MstX; 9.A.66; Debnath et al., 2011; Roosild et al., 2005) is encoded by the gene that precedes yugO. Both play a role in biofilm formation, probably by functioning together (Lundberg et al. 2013; Marino et al. 2015). These K+ channels in bacterial biofilms provide an active, long-range electrical signalling for cellular communities (Prindle et al. 2015).  Metabolic co-dependency gives rise to collective electrical oscillations in biofilms (Liu et al. 2015). This oscillatory electrical signalling, due to periodic release of K+, giving rise to K+ gradients, increasing as swimming cells approach the biofilm that generates the gradiens, allows cells of the same and different speices to find and then incorporate themselves into existing biofilms (Humphries et al. 2017).

Bacteria

BikC of Bacillus subtilis (Q795M8)

 
1.A.1.13.5

Putative 2 TMS ion channel protein (N-terminus) with C-terminal TrkA_N (NADB Rossman) domain.

Actinobacteria

Ion channel protein of Streptomyces coelicolor

 
1.A.1.13.6

Ca2+-activated K+ channel, SynCaK. Functions in the regulation of photosynthesis (Checchetto et al. 2013; Checchetto et al. 2013).

Cyanobacteria

K+ channel of Synechocystis PCC6803

 
1.A.1.13.7

PUtative K+ channel

Cyanobacteria

K+ channel of Synechocystis PCC6803

 
1.A.1.13.8

Potassium channel protein, MjK1 of 333 aas and 6 TMSs. Seems to conduct potassium at low membrane potentials (Hellmer and Zeilinger 2003).

MjK1 of Methanocaldococcus jannaschii (Methanococcus jannaschii)

 
1.A.1.13.9

K+ channel of 387 aas and 2 TMSs, KchA.  KchA is essential for growth at low concentrations of K+. This K+ uptake system is essential for gastric colonization and the persistence of H. pyloriin the stomach (Stingl et al. 2007). This protein is of the two-transmembrane RCK (regulation of K+ conductance) domain family (Stingl et al. 2007).

KchA of Helicobacter pylori

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.14.1

Voltage-activated, Ca2+  channel blocker-inhibited, Na channel, NaChBac (Ren et al., 2001; Zhao et al., 2004Nurani et al, 2008; Charalambous and Wallace, 2011). Transmembrane and extramembrane contributions to thermal stability have been studied (Powl et al., 2012). Deprotonation of arginines in S4 is involved in NaChBac gating (Paldi, 2012). Hinge-bending motions in the pore domain of NaChBac have been reported (Barber et al., 2012).  The C-terminal coiled-coli stabilizes subunit interactions (Mio et al. 2010).  Within the 4 TMS voltage sensor, coupling between residues in S1 and S4 determines its resting conformation (Paldi and Gurevitz 2010). The conserved asparagine was changed to aspartate, N225D, and this substitution shifted the voltage-dependence of inactivation by 25 mV to more hyperpolarized potentials. The mutant also displays greater thermostability (O'Reilly et al. 2017).  Possibly, the side-chain amido group of asn 225 forms one or more hydrogen bonds with different channel elements and that these interactions are important for normal channel function.

Gram-positive bacteria

NaChBac of Bacillus halodurans

 
1.A.1.14.2Voltage-gated Na+ channel, NavPZ (Koishi et al., 2004)Gram-negative bacteriaNavPZ of Paracoccus zeaxanthinifaciens (CAD24429)
 
1.A.1.14.3Na+ channel, NavBP, involved in motility, chemotaxis and pH homeostasis (Ito et al., 2004). NavBP colocalizes with a methyl-accepting chemotaxis protein (MCP) at the cell poles (Fujinami et al., 2007). BacteriaNavBP of Bacillus pseudofirmus (AAT21291)
 
1.A.1.14.4

Voltage-gated Na+ channel, VGSC (Koishi et al., 2004; McCusker et al., 2011) Changing the selectivity filter from LESSM to LDDWSD yielded a Calcium-selective channel (Shaya et al., 2011).

Proteobacteria

VGSC of Silicibacter pomeroyi (56676695)

 
1.A.1.14.5

Voltage-gated Na+ channel, NavCh or NavAb. The 3d-structure is known (3ROW; Payandeh et al., 2011; 4MW3A-D; 4+ selectivity through partial dehydration of Na+ via its direct interaction with conserved glutamate side chains). The pore is preferentially occupied by two ions, which can switch between different configurations by crossing low free-energy barriers (Furini and Domene, 2012). Jiang et al. 2018 presented high-resolution structures of NavAb with the analogous gating-charge mutations that have similar functional effects as in the human channels that cause hypokalaemic and normokalaemic periodic paralysis.  Wisedchaisri et al. 2019 presented a cryo-EM structure of the resting state and a complete voltage-dependent gating mechanism via the voltage sensor (VS). The S4 segment of the VS is drawn intracellularly, with three gating charges passing through the transmembrane electric field. This movement forms an elbow connecting S4 to the S4-S5 linker, tightens the collar around the S6 activation gate, and prevents its opening. This structure supports the classical "sliding helix" mechanism of voltage sensing and provides a complete gating mechanism for voltage sensor function, pore opening, and activation-gate closure based on high-resolution structures of a single sodium channel protein (Wisedchaisri et al. 2019).

(see also TC#s 1.A.1.10.4 and 1.A.1.11.32).

The transport reaction catalyzed by NavCh is:

Na+ (in) ⇌ Na+ (out)

Bacteria

NavCh of Arcobacter butzleri (A8EVM5)

 
1.A.1.14.6

Bacterial voltage-gated sodium channel, Nav.  3-d crystal structures of vaious conformations are known (4P_3A A-D; 4PA7_A-D; 4P9P_A-D. etc.)  (McCusker et al. 2012).  It has its internal cavity accessible to the cytoplasmic surface as a result of a bend/rotation about a central residue in the carboxy-terminal TMS that opens the gate to allow entry of hydrated sodium ions. The molecular dynamics of ion transport through the open conformation has been analyzed (Ulmschneider et al. 2013).  The C-terminal four helix coiled coil bundle domain couples inactivation with channel opining, depedent on the negatively charged linker region (Bagnéris et al. 2013).

Bacteria

Nav of Magnetococcus marinus (also called sp. strain MC-1)

 
1.A.1.14.7

Tetrameric 6 TMS subunit Na+ channel protein, NaV.  Two low resolution cyroEM structures revealed two conformations reconstituted in lipid bilayers (Tsai et al. 2013). Despite a voltage sensor arrangement identical with that in the activated form, Tsai et al. 2013 observed two distinct pore domain structures: a prominent form with a relatively open inner gate, and a closed inner-gate conformation similar to the first prokaryotic Nav structure. Structural differences, together with mutational and electrophysiological analyses, indicated that widening of the inner gate was dependent on interactions among the S4-S5 linker, the N-terminal part of S5 and its adjoining part in S6, and on interhelical repulsion by a negatively charged C-terminal region subsequent to S6 (Tsai et al. 2013).

Firmicutes

Nav of Caldalkalibacillus thermarum

 
1.A.1.14.8

Voltage-gated Na+ channel, Nsv, of 277 aas and 6 TMSs with a structually defined C-terminal regulatory domain (Miller et al. 2016). Voltage-gated sodium channels (NaVs) are activated by transiting the voltage sensor from the deactivated to the activated state. Tang et al. 2017 identified peptide toxins stabilizing the deactivated VSM of bacterial NaVs. A cystine knot toxin, called JZTx-27, from the venom of the tarantula Chilobrachys jingzhao proved to be a high-affinity antagonist. JZTx-27 stabilizes the inactive form of the voltage sensor, thereby inhibiting channel activity (Tang et al. 2017).

Nsv of Bacillus alcalophilus

 
1.A.1.14.9

Bacterial type voltage-activated sodium channel of 718 aas, NaV.

NaV of Phaeodactylum tricornutum

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.15.1

6 TMS basolateral tracheal epithelial cell/voltage-gated, small conductance, K+ α-chain) [acts with the KCNE3 β-chain]. Mutations in human Kv7 genes lead to severe cardiovascular and neurological disorders such as the cardiac long QT syndrome and neonatal epilepsy (Haitin and Attali, 2008). KCNE3 can co-assemble with KCNQ1 (1.A.1.15.6) (Kang et al., 2010). KCNQ1 regulates insulin secretion in  the MIN6 beta-cell line (Yamagata et al., 2011).  The S4-S5 linker of KCNQ1 forms a scaffold with S6 controlling gate closure (Labro et al. 2011).  The KCNQ1 channel is differentially regulated by KCNE1 and KCNE2 (Li et al. 2014Slow-activating channel complexes formed by KCNQ1 and KCNE1 are essential for human ventricular myocyte repolarization, while constitutively active KCNQ1-KCNE3 channels are important in the intestine. Inherited sequence variants in human KCNE1 and KCNE3 cause cardiac arrhythmias but by different mechanisms, and each is important for hearing in unique ways (Abbott 2015). The topology and dynamics of the voltage sensor domain of KCNQ1 reconstituted in a lipid bilayer environment has been studied (Dixit et al. 2019).

Mammals

KCNQ1 K+ channel of Mus musculus

 
1.A.1.15.2

    6 TMS voltage-gated K channel, KCNQ2 or Kv7.2.  Mutations cause benign familial neonatal convulsions (BNFC; epilepsy; Maljevic et al. 2016).  It forms homotetramers or heterotetramers with KCNQ3/Kv7.3) (Soldovieri et al., 2006; Uehara et al., 2008)). Like all other Kv7.2 channels, it is activated by phosphatidyl inositol-4,5-bisphosphate and hence can be regulated by various neurotransmitters and hormones (Telezhkin et al. 2013).  Gating pore currents that go through the gating pores in TMSs1-4 (the voltage sensor) may give rise to peripheral nerve hyperexcitability (Moreau et al. 2014). Retigabine and ICA73, two anti-epileptic drugs, act via distinct mechanisms due to interactions with specific residues that underlie subtype specificity of KCNQ channel openers (Wang et al. 2016). A  tight spatial and functional relationship between the DAT/GLT-1 transporters and the Kv7.2/7.3 potassium channel immediately readjusts the membrane potential of the neuron, probably to limit the neurotransmitter-mediated neuronal depolarization (Bartolomé-Martín et al. 2019). E-2-dodecenal from cilantro (Coriandrum sativum) is a potent activator and anticonvulsant that binds with an affinity of 60 nM to TMS5 in several KCNQ channels including KCNQ2 and 3 (Manville and Abbott 2019).

Mammals

KCNQ2 K+ channel of Homo sapiens (O43526)

 
1.A.1.15.3

6 TMS voltage-gated K+ channel, KCNQ3 or Kv7.3.  Mutations cause benign familial neonatal convulsions (BNFC; epilepsy; Maljevic et al. 2016). Forms homotetramers or heterotetramers with KCNQ2 (Soldovieri et al., 2006; Uehara et al., 2008).  Retigabine and ICA73, two anti-epileptic drugs, act via distinct mechanisms due to interactions with specific residues that underlie subtype specificity of KCNQ channel openers (Wang et al. 2016). Gabapentin at low concentrations is a activator of KCNQ3, KCNQ2/3 and KCNQ5 but not KCNQ2 or KCNQ4 (Manville and Abbott 2018). At high concentrations it can be inhibitory.  A  tight spatial and functional relationship between the DAT/GLT-1 transporters and the Kv7.2/7.3 potassium channel immediately readjusts the membrane potential of the neuron, probably to limit the neurotransmitter-mediated neuronal depolarization (Bartolomé-Martín et al. 2019). E-2-dodecenal from cilantro (Coriandrum sativum) is a potent activator and anticonvulsant that binds with an affinity of 60 nM to TMS5 in several KCNQ channels including KCNQ2 and 3 (Manville and Abbott 2019).

Mammals

KCNQ3 K+ channel of Homo sapiens (O43525)

 
1.A.1.15.4

6 TMS cell volume sensitive, voltage-gated K+ channel, KCNQ4 or Kv7.4 (mutations cause DFNA2, an autosomal dominant form of progressive hearing loss) (forms homomers or heteromers with KCNQ3) (localized to the basal membrane of cochlear outer hair cells and in several nuclei of the central auditory pathway in the brainstem). Four splice variants form heterotetramers; each subunit has different voltage and calmodulin-sensitivities (Xu et al., 2007).  Autosomal dominant mutant forms leading to progressive hearing loss (DFNA2) have been characterized (Kim et al. 2011). Phosphatidylinositol 4,5-bisphosphate (PIP2) and polyunsaturated fatty acids (PUFAs) impact ion channel function (Taylor and Sanders 2016).

Mammals

KCNQ4 K+ channel of Homo sapiens

 
1.A.1.15.5

The KCNQ5 K+ channel (modulated by Zn2+ , pH and volume change) (Jensen et al., 2005).  A triple cysteine module within M-type K+ channels mediates reciptrocal channel modulation by nitric oxide and reactive oxygen species (Ooi et al. 2013). Gabapentin at low concentrations is a activator of KCNQ3, KCNQ2/3 and KCNQ5 but not of KCNQ2 or KCNQ4 (Manville and Abbott 2018). At high concentrations, it can be inhibitory.

Animals

KCNQ5 of Mus musculus
(Q9JK45)

 
1.A.1.15.6

K+ voltage-gated channel, LQT-like subfamily; Kv7.1; KvLQT1. KCNQ1 (regulated by KCNE peptides (TC# 8.A.58) affect voltage sensor equilibrium (Rocheleau and Kobertz, 2007). Almost 300 mutations of KCNQ1 have been identified in patients, and most are linked to the long QT syndrome (LQT1), some in the voltage sensor (Peroz et al., 2008; Eldstrom et al. 2010; Qureshi et al. 2013; Ikrar et al. 2008). KCNQ1-KCNE1 complexes may interact intermittently with the actin cytoskeleton via the C-terminal region (Mashanov et al., 2010). The stoichiometry of the KCNQ1 - KCNE1 complex is flexible, with up to four KCNE1 subunits associating with the four KCNQ1 subunits of the channel (Nakajo et al., 2010). A familial mutation in the voltage-sensor of the KCNQ1 channel results in a cardiac phenotype (Henrion et al., 2012). KCNQ1 regulates insulin secretion in the MIN6 beta-cell line (Yamagata et al., 2011; Gofman et al., 2012).  Electrostatic interactions of S4 arginines with E1 and S2 contribute to gating movements of S4, but coupling requires the lipid phosphatidylinositol 4,5-bisphosphate (PIP2) as voltage-sensing domain activation failed to open the pore in the absence of PIP2 (Zaydman et al. 2013). The D242N mutation causes impaired action potential adaptation to exercise and an increase in heart rate. Moreover, the D242 amino acylposition is involved in the KCNE1-mediated regulation of the voltage dependence of activation of the KV7.1 channel (Moreno et al. 2017). The KCNQ1 channel interacts with MinK (KCNE1) to cause pore constriction, generating the slow delayed rectifier (IKs) current in the heart (Jalily Hasani et al. 2018). KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity (Harkcom et al. 2019). Activation of the neuronal Kv7/KCNQ/M-current represents an attractive therapeutic strategy for treatment of hyperexcitability-related neuropsychiatric disorders such as epilepsy, pain, and depression, and channel openers for treatment of antiepilepsy have been developed (Zhang et al. 2019). The relationship between mutation locations in KCNQ1, which is a major gene in long QT syndrome (LQTS), and phenotype has been analyzed and used for risk stratification (Yagi et al. 2018).

Animals

KCNQ1 of Homo sapiens (P51787)

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.16.1

The small conductance Ca2+-activated K+ channel, SkCa2, Sk2 or Kcnn2 (not inhibited by arachidonate) (activated by three small organic molecules, the 1-EBIO and N5309 channel enhancers and the DCEBIO channel modulation (Pedarzani et al., 2005)).  It is inhibited by protonation of outer pore histidine residues (Goodchild et al., 2009). The same is true for SK3 (K(Ca) 2.3 (Q9UGI6)). Regulates endothelial vascular function (Sonkusare et al., 2012).  Distinct subcellular mechanisms enhance the surface membrane expression by its interacting proteins, α-actinin 2 (TC# 8.A.66.1.3) and filamin A (TC# 8.A.66.1.4) (Zhang et al. 2016). SK channel activators can compensate for age-related changes of the autorhythmic functions of the cerebellum (Karelina et al. 2017). SK2 proteins are more abundant in Purkinje cells than in the ventricular myocytes of normal rabbit ventricles (Reher et al. 2017). Apamin inhibits and isoproterenol activates this and other SK (KCNN) channels, and activation by isoproterenol is sex-dependent (Chen et al. 2018).  Diverse interactions between KCa and TRP channels integrate cytoplasmic Ca2+, oxidative, and electrical signaling affecting cardiovascular physiology and pathology (Behringer and Hakim 2019).

Mammals

SkCa2 of Homo sapiens

 
1.A.1.16.2

The intermediate conductance, Ca2+-activated K+ channel, Kcnn4, SK4, Sk4, Smik, Ik1 hIK1, IKCa or KCa3.1, also called the Gardos channel (inhibited by 1 μM arachidonate which binds in the pore (Hamilton et al., 2003)). Nucleoside diphosphate kinase B (NDPK-B) activates KCa3.1 via histidine phosphorylation, resulting in receptor-stimulated Ca2+ flux and T cell activation (Di et al., 2010). Regulates endothelial vascular function (Sonkusare et al., 2012).  Tissue-specific expression of splice variants of the orthologous rat KCNN4 protein have been reported (Barmeyer et al. 2010).  Residues involved in gating have been identified (Garneau et al. 2014). Also present in the inner mitochondrial membrane where increases of mitochondrial matrix [Ca2+] cause mtKCa3.1 opening, thus linking inner membrane K+ permeability and transmembrane potential to Ca2+ signalling (De Marchi et al. 2009). KCa3.1 (IKCa) channels are expressed in CA1 hippocampal pyramidal cells and contribute to the slow afterhyperpolarization that regulates spike accommodation (Turner et al. 2016). SK channel activators can compensate for age-related changes of the autorhythmic functions of the cerebellum (Karelina et al. 2017). The activation mechanism has been revealed by the cryoEM structure of the SK4-calmodulin complex (Lee and MacKinnon 2018).  It is responsible for hyperpolarization in some tumor cells (Lazzari-Dean et al. 2019). Mutations are linked to dehydrated hereditary stomatocytosis (xerocytosis) (Andolfo et al. 2015).

Mammals

hIK1 of Homo sapiens (AAC23541)

 
1.A.1.16.3

Small conductance calcium-gated potassium (SK) channel. Three charged residues in TMS S6 of SK channels near the inner mouth of the pore collectively control the conductance and rectification through an electrostatic mechanism (Li and Aldrich, 2011).

Animals

SK of Drosophila melanogaster (Q7KVW5)

 
1.A.1.16.4
Small conductance Ca2+-activated K+ channel, KCNL-2 of 672 aas.  Plays a role in the rate of egg laying (Chotoo et al. 2013).

Animals

KCNL-2 of Caenorhabditis elegans

 
1.A.1.16.5

Plasma membrane small conductance calcium-activated K+ channel of 396 aas, TSKCa; probably involved in immunoregulation (Cong et al. 2009).

Animals (fish)

TSKCa of Psetta maxima (Turbot) (Pleuronectes maximus)

 
1.A.1.16.6

Small conductance calcium-activated K+ channel of 543 aas. KCNN1 or SK

SK of Homo sapiens

 
1.A.1.16.7

Small conductance calcium-activated potassium channel protein 3 of 736 aas and 6 TMSs, SK3 or KCNN3.

KCNN3 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.17.1

The archaeal voltage-regulated K channel, KvAP (Ruta et al., 2003). X-ray and solution structures are available. The latter shows phospholipid interactions with the isolated voltage sensor domain (Butterwick and MacKinnon 2010; Li et al. 2014). The gating-charge arginine in TMS4 of the voltage sensor forms part of the helical hairpin "paddle", and it moves 15-20 Å through the membrane to open the pore (Ruta et al., 2005). The orientation and depth of insertion of the voltage-sensing S4 helix has been determined (Doherty et al., 2010). A synthetic S6 segment derived from the KvAP channel self-assembles, permeabilizes lipid vesicles, and exhibits ion channel activity in bilayer lipid membrane (Verma et al., 2011).  Thus the gating mechanism combines structural rearrangements and electric-field remodeling ( Li et al. 2014).  KvAP has been reconstituted in Giant Unilamellar Vesicles (GUVs) (Garten et al. 2015).  TMS4 (S4) which senses voltage also promotes membrane insertion of the voltage-sensor domain (Mishima et al. 2016). KvAP has a configuration consistent with a water channel, possibly underlying the conductance of protons, and other cations, through voltage-sensor domains (Freites et al. 2006). The structural dynamics of the paddle motif loop in the activated conformation of the KvAP voltage sensor have been studied from biophysical standpoints (Das et al. 2019).

Archaea

KvAP of Aeropyrum pernix (Q9YDF8) 

 
1.A.1.17.2Voltage-gated K+ channel, Kv (Santos et al., 2008).

Bacteria

Kv of Listeria monocytogenes (Q8Y5K1)

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.18.1

The two-pore domain potassium channel, TRESK-1 (Czirjak et al., 2004) (provides the background K+ current in mouse DRG neurons (Dobler et al., 2007)) TRESK (TWIK-related spinal cord K+ channel) is reversibly activated by the calcium/calmodulin-dependent protein phosphatase, calcineurin. Czirjak et al. 2008 reported that 14-3-3 proteins directly bind to the intracellular loop to TRESK and control the kinetics of the calcium-dependent regulation. Cloxyquin (5-chloroquinolin-8-ol) is an activator (Wright et al. 2013).  A cytoplasmic loop binds tubulin (Enyedi et al. 2014). Channel activity is modified by phosphorylation (inactive) and dephosphorylation (active) of the unusually long intracellular loop between the 2nd and 3rd TMS (Lengyel et al. 2018).

Animals

TRESK-1 of Mus musculus (AAQ91836)

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.19.1

Alkalinizatioin-activated Ca2+-selective channel, sperm-associated cation channel, CatSper, required for male fertility and the hyperactivated motility of spermatozoa (Kirichok et al. 2006). These channels require auxiliary subunits, CatSperβ, γ and δ for activity (Chung et al., 2011).  The primary channel protein is CatSper1 (Liu et al., 2007).  CatSper1 may be a target for immunocontraception (Li et al. 2009). CatSper channels regulate sperm motility (Vicente-Carrillo et al. 2017). Sperm competition is selective for a disulfide-crosslinked macromolecular architecture. CatSper channel opening occurs in response to pH, 2-arachidonoylglycerol, and mechanical force. A flippase function is hypothesized, and a source of the concomitant disulfide isomerase activity is found in CatSper-associated proteins beta, delta and epsilon (Bystroff 2018).

Mammals

CatSper of Homo sapiens
CatSper1 (Q96P76)
CatSper3 (Q86XQ3)
CatSper4 (Q7RTX7)
CatSperβ (Q9H7T0)
CatSperγ (Q6ZRH7)
CatSperδ (Tmem146) (Q86XM0)
CatSperε (B1AQM6)

 
1.A.1.19.2Sperm-associated cation channel, CatSper2 (6 TMS Ca2+ channel)MammalsCatSper2 of Homo sapiens (26051223)
 
1.A.1.19.3

Alkalinization-activated Ca2+-selective channel, Cation channel of sperm 1, CatSper1, required for male fertility and the hyperactivated motility of spermatozoa. These channels require auxiliary subunits, CatSper β, γ and δ for activity (Chung et al., 2011; Liu et al., 2007).

Animals

CatSper of Mus musculus
CatSper1 (Q91ZR5)
CatSper3 (Q86XQ3)
CatSper4 (Q8BVN3)
CatSperβ (Q8C0R2)
CatSperγ (C6KI89)
CatSperδ (Tmem146) (E9Q9F6) 

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.2.1

Voltage-sensitive K+ channel (PNa+/PK+ ≈ 0.1) Shaker and Shab K+ channels are blocked by quinidine (Gomez-Lagunas, 2010).

Animals

Shab11 of Drosophila melanogaster

 
1.A.1.2.10

Voltage-gated K+ channel, chain A, Shaker-related, Kv1.2 (Crystal structure known, Long et al., 2007; Chen et al. 2010). Functions with the auxiliary subunit, Ivβ1.2; 8.A.5.1.1) (Peters et al. 2009).  Delemotte et al. (2010) described the effects of sensor domain mutations on molecular dynamics of Kv1.2.  The Sigma 1 receptor (Q99720; Sigma non-opioid intracellular receptor 1) interacts with Kv1.2 to shape neuronal and behavioral responses to cocaine (Kourrich et al. 2013).  Amino acid substitutions cause Shaker to become heat-sensing (opens with increasing temperature as for TrpV1) or cold-sensing (opens with decreasing temperature as for TrpM8) (Chowdhury et al. 2014).  The Shaker Kv channel was truncated after the 4th transmembrane helix S4 (Shaker-iVSD) which showed altered gating kinetics and formed a cation-selective ion channel with a strong preference for protons (Zhao and Blunck 2016).  Direct axon-to-myelin linkage by abundant KV1/Cx29 (TC# 1.A.24.1.12) channel interactions in rodent axons supports the idea of an electrically active role for myelin in increasing both the saltatory conduction velocity and the maximal propagation frequency in mammalian myelinated axons (Rash et al. 2016). A cryoEM structure (3 - 4 Å resolution; paddle chimeric channel; closed form) in nanodiscs has been determined (Matthies et al. 2018). Possible gating mechanisms have been discussed (Kariev and Green 2018; Infield et al. 2018).

Animals

Kv1.2 of Homo sapiens (P16389)

 
1.A.1.2.11

Voltage-gated K+ channel, Shab-related, Kv2.1 or KCNB1 (858aas) The crystal structure is known (Long et al., 2007). Rat Kv2.1 and Kv2.2 (long) are colocalized in the somata and proximal dendrites of cortical pyramidal neurons and are capable of forming functional heteromeric delayed rectifier channels. The delayed rectifer currents, which regulate action potential firing, are encoded by heteromeric Kv2 channels in cortical neurons (Kihira et al., 2010). Phosphorylation by AMP-activated protein kinase regulates membrane excitability (Ikematsu et al., 2011). Functional interactions between residues in the S1, S4, and S5 domains of Kv2.1 have been identified (Bocksteins et al., 2011).  Missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminus cause neurodevelopmental disorders, sometimes with seizures (de Kovel et al. 2017).  Kv2.1 channels consist of two types of alpha-subunits: (1) electrically-active Kcnb1 alpha-subunits and (2) silent or modulatory alpha-subunits plus beta-subunits that, similar to silent alpha-subunits, regulate electrically-active subunits (Jędrychowska and Korzh 2019). It plays a role  in neurodevelopmental disorders, such as epileptic encephalopathy. The N- and C-terminal domains of the alpha-subunits interact to form the cytoplasmic subunit of hetero-tetrameric potassium channels. Kcnb1-containing channels are involved in brain development and reproduction.

Animals

Kv2.1/Kv2.2 of Homo sapiens
(Q14721)
(Q92953)

 
1.A.1.2.12

Voltage-gated K+ channel, Kv1.1 or KCNA1. It is palmitoylated, modulating voltage sensing (Gubitosi-Klug et al. 2005). It is regulated by syntaxin through dual action on channel surface expression and conductance (Feinshreiber et al., 2009).  Defects cause episodic ataxia type 1 (EA1), an autosomal dominant K+ channelopathy accompanied by short attacks of cerebellar ataxia and dysarthria (D'Adamo et al. 2014). Direct axon-to-myelin linkage by abundant KV1/Cx29 channel interactions in rodent axons supports the idea of an electrically active role for myelin in increasing both the saltatory conduction velocity and the maximal propagation frequency in mammalian myelinated axons (Rash et al. 2016). Kv1.1 is present in bull sperm where it is necessary for normal sperm progressive motility, per cent capacitated spermatozoa (B-pattern) and the acrosome reaction (Gupta et al. 2018). Gating induces large aqueous volumetric remodeling (Díaz-Franulic et al. 2018).

Animals

Kv1.1 of Homo sapiens (Q09470)

 
1.A.1.2.13

Voltage-gated K+ channel subfamily C member 3, Kv3.3. Negatively modulated by protein kinase C (Desai et al., 2008). Phosphorylation of Kv3.3 by PKC may allow neurons to maintain action potential height during stimulation at high frequencies, and therefore contributes to stimulus-induced changes in the intrinsic excitability of neurons such as those of the auditory brainstem (Desai et al., 2008).  N-glycosylation impacts the sub-plasma membrane localization and activity of Kv3.1b-containing channels, and N-glycosylation processing of Kv3.1b-containing channels contributes to neuronal excitability (Hall et al. 2017).

Animals

Kv3.3 of Homo sapiens (Q14003)

 
1.A.1.2.14

Voltage-gated delayed rectifier K+ channel, Kv1 of the octopus. RNA editing underlies adaption (Garrett and Rosenthal, 2012).  94% identical to the squid giant axon delayed rectifier voltage-dependent potassium channel, SqKv1A (Q25376).

Animals

Kv1 of Octopus vulgaris (H2EZS9)

 
1.A.1.2.15Potassium voltage-gated channel subfamily S member 3 (Delayed-rectifier K(+) channel alpha subunit 3) (Voltage-gated potassium channel subunit Kv9.3)AnimalsKCNS3 of Homo sapiens
 
1.A.1.2.16Potassium voltage-gated channel subfamily S member 2 (Delayed-rectifier K(+) channel alpha subunit 2) (Voltage-gated potassium channel subunit Kv9.2)AnimalsKCNS2 of Homo sapiens
 
1.A.1.2.17

Potassium voltage-gated channel (KCNH) subfamily G member 3 (Voltage-gated potassium channel subunit Kv10.1) (Voltage-gated potassium channel subunit Kv6.3).  Splice variants have different properties and can activate cyclin-dependent protein kinases (Ramos Gomes et al. 2015). Control of transport (pore) function  by the voltage sensor may involve more than one mechanism (Tomczak et al. 2017).  The silent (non transporting) behaviour of Kv6.3 in the ER is caused by the C-terminal part of its sixth transmembrane domain that causes ER retentio (Ottschytsch et al. 2005).

Animals

Kcng3 or Kv10.1of Rattus norvegicus

 
1.A.1.2.18Potassium voltage-gated channel subfamily F member 1 (Voltage-gated potassium channel subunit Kv5.1) (kH1)AnimalsKCNF1 of Homo sapiens
 
1.A.1.2.19

The voltage-gated K+ channel subfamily D member 3, KCND3 or Kv4.3.  Mutations cause spinocerebellar ataxia type 19 (Duarri et al. 2012). Positively charged residues in S4 contribute to channel inactivation and recovery (Skerritt and Campbell 2007). The crystal structure of Kv4.3 with its regulatory subunit, Kchip1, has been solved (2NZ0) (Wang et al. 2007).

Animal

KCND3 of Homo sapiens

 
1.A.1.2.2

Voltage-sensitive K+ channel

Animals

Shaw2 of Drosophila melanogaster

 
1.A.1.2.20

Shaker K+ channel, Shk-1, Shk1, Kv1 of 536 aas and 6 TMSs.  Mediates the voltage-dependent potassium ion permeability of excitable membranes. Has an important role in repolarization and in regulating the pattern of action potential firing. Isoform a expresses currents in a more depolarized voltage range than isoform d (Liu et al. 2011).

Shk-1 of Caenorhabditis elegans

 
1.A.1.2.21

Shal (SHL-1, Kv4) K+ channels of 578 aas and 6 TMSs are the predominant transient outward current in C. elegans muscle. SHL-1 expression occurs in a subset of neurons, body wall muscle and in male-specific diagonal muscles (Fawcett et al. 2006) and control the excitability of neurons and cardiac myocytes by conducting rapidly activating-inactivating currents. Activity is modulated by three K+ channel interacting (KChIP) soluble auxiliary subunits, NCS-4, NCS-5, and NCS-7. All three ceKChIPs alter electrical characteristics of SHL-1 currents by slowing down inactivation kinetics and shifting voltage dependence of activation to more hyperpolarizing potentials. Native SHL-1 current is completely abolished in cultured myocytes of Triple KO worms in which all three KChIP genes are deleted (Chen et al. 2015).

Shal of Caenorhabditis elegans

 
1.A.1.2.22

K+ channel, jShak1 of 487 aas and 6 TMSs. Intramolecular interactions control voltage sensitivity (Sharmin and Gallin 2016).

jShak1 of Polyorchis penicillatus (Hydromedusa; jellyfish)

 
1.A.1.2.23

Voltage-gated potassium channel subunit Kv8.2, KCNC2, of 545 aas and 6 TMSs. Mutation causes central ellipsoid loss which involves cone dystrophy with supernormal rod electroretinogram. It is a monogenic disease due to KCNV2 gene mutations that affect KCNC2 channel function in rod and cone photoreceptors (Xu et al. 2017).

KCNC2 of Homo sapiens

 
1.A.1.2.24

Voltage-gated K+ channel, KCNC1 (Kv3.1) of 511 aas and 6 TMSs.  It plays an important role in the rapid repolarization of fast-firing brain neurons. The channel opens in response to the voltage difference across the membrane, forming a potassium-selective channel through which potassium ions pass in accordance with their electrochemical gradient (Muona et al. 2015). Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNC2 (TC# 1.A.1.2.23), and possibly other family members as well. Contributes to fire sustained trains of very brief action potentials at high frequency in pallidal neurons. Causes various genetic neurological disorders when functioning abnormally such as attention deficit/hyperactivity (Yuan et al. 2017), myoclonus epilepsy and ataxia (Oliver et al. 2017) and intellectual disability (Poirier et al. 2017). The lipid environment, including 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC) and tetracosanoic acid (C24:0) affects Kv3.1b channel expression/functionality (Bezine et al. 2018).

 

KCNC1 of Homo sapiens

 
1.A.1.2.25

Potassium voltage-gated channel subfamily B member 2, Kv2.2 or KCNB2 of 911 aas and 6 TMSs.

Kv2.2 of Homo sapiens

 
1.A.1.2.26

Potassium voltage-gated channel subfamily G member 4, KCNG4, of 519 aas and 6 TMSs.  Potassium channel subunit that does not form functional channels by itself, but can form functional heterotetrameric channels with KCNB1; modulates the delayed rectifier voltage-gated potassium channel activation and deactivation rates of KCNB1 (Mederos Y Schnitzler et al. 2009).

KCNG4 of Homo sapiens

 
1.A.1.2.27

Potassium voltage-gated channel subfamily G member 1, KCNG1, of 513 aas and 6 TMSs. Expressed in brain and placenta, and at much lower levels in kidney and pancreas (Su et al. 1997). This potassium channel subunit does not form functional channels by itself, but can form functional heterotetrameric channels with KCNB1. It modulates the delayed rectifier voltage-gated potassium channel activation and deactivation rates of KCNB1 (Mederos Y Schnitzler et al. 2009).

KCNG1 of Homo sapiens

 
1.A.1.2.28

Potassium voltage-gated channel subfamily D member 1, Kv4.1 of 647 aas and 6 TMSs.  Pore-forming α-subunit of a voltage-gated rapidly inactivating A-type potassium channel. It may contribute to I(To) current in the heart and I(Sa) current in neurons. Channel properties are modulated by interactions with other α-subunits and with regulatory subunits, KChIP-1 and DPPX-S. The complex voltage-dependent gating rearrangements are not limited to the membrane-spanning core but must include the intracellular T1-T1 tetramerization domains interface (Wang and Covarrubias 2006).

 

Kv4.1 of Homo sapiens

 
1.A.1.2.29

K+ channel of 529 aas and 6 TMSs, Kv1.6 or KCNA6. It can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA6, and possibly other family members (). channel properties depend on the type of alpha subunits that are part of the channel. Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation (By similarity). Homotetrameric channels display rapid activation and slow inactivation (Grupe et al. 1990). It is inhibited by 0.6 μM β-defensin 3 (BD3) (Zhang et al. 2018) as well as by neurotoxic cone snail peptide μ-GIIIA and other conotoxins (Leipold et al. 2017).

Kv1.6 of Homo sapiens

 
1.A.1.2.3

Voltage-sensitive fast transient outward current K+ channel in neurons and muscle of flies and worms (Fawcett et al., 2006)

Animals

Shal2 of Drosophila melanogaster

 
1.A.1.2.30

Potassium channel protein of 542 aas and 10 TMSs in a 2 + 2 + 6 TMS toplogy, where the last 6 TMSs comprise the voltage-gated K+ channel.

K+ channel of Haloplasma contractile

 
1.A.1.2.31

The KCNA4 OR Kv1.4 K+ channel of 653 aas and 6 TMSs (potassium voltage-gated channel subfamily A member 4).  The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (Ramaswami et al. 1990); Po et al. 1993).It can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCNA1, KCNA2, KCNA4, KCNA5, and possibly other family members; channel properties depend on the type of alpha subunits that are part of the channel (Po et al. 1993). Channel properties are modulated by cytoplasmic beta subunits that regulate the subcellular location of the alpha subunits and promote rapid inactivation. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes. The Molecular basis involved in the blocking effect of the antidepressant, metergoline, on C-type inactivation has been reported (Bai et al. 2018). The molecular basis for the inactivation of the channel by the antidepressant, metergoline, has been presented (Bai et al. 2018).

 

KCNA4 of Homo sapiens

 
1.A.1.2.4

Margatoxin-sensitive voltage-gated K+ channel, Kv1.3 (in plasma and mitochondrial membranes of T lymphocytes) (Szabò et al., 2005). Kv1.3 associates with the sequence similar (>80%) Kv1.5 protein in macrophage forming heteromers that like Kv1.3 homomers are r-margatoxin sensitive (Vicente et al., 2006). However, the heteromers have different biophysical and pharmacological properties. The Kv1.3 mitochondrial potassium channel is involved in apoptotic signalling in lymphocytes (Gulbins et al., 2010). Interactions between the C-terminus  of Kv1.5 and Kvβ regulate pyridine nucleotide-dependent changes in channel gating (Tipparaju et al., 2012).  Intracellular trafficking of the KV1.3 K+ channel is regulated by the pro-domain of a matrix metalloprotease (Nguyen et al. 2013).  Direct binding of caveolin regulates Kv1 channels and allows association with lipid rafts (Pérez-Verdaguer et al. 2016). Addtionally, NavBeta1 interacts with the voltage sensing domain (VSD) of Kv1.3 through W172 in the transmembrane segment to modify the gating process (Kubota et al. 2017). During insertion of Kv1.3, the extended N-terminus of the second α-helix, S2, inside the ribosomal tunnel is converted into a helix in a transition that depends on the nascent peptide sequence at specific tunnel locations (Tu and Deutsch 2017). The microRNA, mmumiR449a, reduced the mRNA expression levels of transient receptor potential cation channel subfamily A member 1 (TRPA1), and calcium activated potassium channel subunit alpha1 (KCNMA1) and increased the level of transmembrane phosphatase with tension homology (TPTE) in the DRG cells (Lu et al. 2017). This channel is regulation by sterols (Balajthy et al. 2017). Loss of function causes atrial fibrillation, a rhythm disorder characterized by chaotic electrical activity of cardiac atria (Olson et al. 2006). The N-terminus and S1 of Kv1.5 can attract and coassemble with the rest of the channel (i.e. Frag(304-613)) to form a functional channel independently of the S1-S2 linkage (Lamothe et al. 2018).

Animals

Kv1.3 homomers and Kv1.3/Kv1.5 heteromers of Homo sapiens (P22001)
Kv1.3 (P22001)
Kv1.5 (P19024)

 
1.A.1.2.5

Voltage-gated K+ channel subfamily D, member 2, Kv4.2 or KCND2, in neurons and muscle; forms complexes with auxiliary subunits and scaffolding proteins via its N-terminus, influencing trafficking, temperature-sensitivity and gating (Radicke et al. 2013).These subunits are (1) dipeptidyl-peptidase-like type II transmembrane proteins typified by DPPX-S (e.g., protein 6, P42658; 865 aas), and (2) cytoplasmic Ca2+ binding proteins known as K+ channel interacting proteins (KChIPs; TC#5.B.1.1.7; Q6PIL6) (Seikel and Trimmer 2009).  The C-terminus interacts with KChIP2 to influence gating, surface trafficking and gene expression (Han et al., 2006; Schwenk et al., 2008). KChIPs (250 aas for mouse KChIP4a; Q6PHZ8) are homologous to domains in NADPH oxidases (5.B.1). Heteropoda toxin 2 (P58426; PDB 1EMX; TC#8.B.5.2.2) interactions with Kv4.3 and Kv4.1 give rise to differences in gating modifications (DeSimone et al., 2011).  Mutations cause autism and seizures due to a slowing of channel inactivation (Lee et al. 2014).  The stoichiometry of Kv4.2 and DPP6 is 4:4 (Soh and Goldstein 2008). Neferine, an isoquinoline alkaloid from plants, inhibits Kv4.3 channels, probably by blocking the open state (Wang et al. 2015). SUMOylating (derivatizing with small ubiquitin-like modifier) two distinct sites on Kv4.2, increases surface expression and decreases current amplitude (Welch et al. 2019).

Animals

Kv4.2 of Homo sapiens (Q9NZV8)

 
1.A.1.2.6

Voltage-gated K+ channel, Shaker. Shaker and Shab K+ channels are blocked by quinidine (Gomez-Lagunas, 2010). Also regulated by unsaturated fatty acids (Börjesson and Elinder, 2011).  TMSs 3 and 4 comprise the voltage sensor paddle (Xu et al. 2013).  Partially responsible for action potential repolarization during synaptic transmission (Ford and Davis 2014). Shaker K+ channels can be mutated in S4 to create an analogous ""omega"" pore (Held et al. 2018). The NMR structure of the isolated Shaker voltage-sensing domain in LPPG Micelles has been reported (Chen et al. 2019).

	

Animals

Shaker of Drosophila melanogaster (CAA29917)

 
1.A.1.2.7

Electrically silent lens epithelium K+ channel (Delayed rectifier K+ channel α-subunit, Kv9.1 (Shepard & Rae, 1999))

Animals

Kv9.1 of Homo sapiens
(Q96KK3)

 
1.A.1.2.8

Voltage gated K+ channel/MiNK related peptide (MiRP) complex, KVS1(α)/MPS-1/MiRPβ (expressed in chemo- and mechano-sensory neurons. Involved in chemotaxis, mechanotransduction and locomotion (Bianchi et al., 2003)). KVS-1 and KVS-2 are homologous; MPS-1 is member of the MiNK family (8.A.10). KVS-1/MPS-1 association involves hydrophobic forces (Wang and Sesti, 2007).

Animals

KVS-1 (α)/ MPS-1 (MiRPβ) of Caenorhabditis elegans
KVS-1 (α) (Q86GI9)
MPS-1 (MiRPβ) (Q86GJ0)

 
1.A.1.2.9

Brain-specific regulatory α-chain homologue that coassembles with other α-subunits to form active heteromultimeric K+ channels of unique kinetic properties, Kv2.3r. The functional expression of this regulatory α-subunit represents a novel mechanism without precedents in voltage-gated channels, which contributes to the functional diversity of K+ channels (Castellano et al., 1997). Beta subunits regulate the response of human Kv4.3 to protein kinae C phosphorylation and provide a potential mechanism for modifying the response of ion conductance to alpha-adrenergic regulation in vivo (Abbott 2017).

Animals

Kv2.3r of Rattus norvegicus (P97557)

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.20.1

K+ voltage-gated ether-a-go-go-related channel, H-ERG (KCNH2; Erg; HErg; Erg1, Kv11.1) subunit Kv11.1 (long QT syndrome type 2) (Gong et al., 2006; Chartrand et al. 2010; McBride et al. 2013).  Forms a heteromeric K+ channel regulating cardiac repolarization, neuronal firing frequency and neoplastic cell growth (Szabó et al., 2011). Oligomerization is due to N-terminal interactions between two splice variants, hERG1a and hERG1b (Phartiyal et al., 2007). Structure function relationships of ERG channel activation and inhibition have been reviewed (Durdagi et al., 2010). Interactions between the N-terminal domain and the transmembrane core modulate hERG K channel gating (Fernández-Trillo et al., 2011). The marine algal toxin azaspiracid is an open state blocker (Twiner et al., 2012). Verapamil blocks channel activity by binding to Y652 and F656 in TMS S6 (Duan et al. 2007).  Hydrophobic interactions between the voltage sensor and the channel domain mediate inactivation (Perry et al. 2013), but voltage sensing by the S4 segment can be transduced to the channel gate in the absence of physical continuity between the two modules (Lörinczi et al. 2015).  Mutations give rise to long QT syndrome (Osterbur et al. 2015).  Polyphenols such as caffeic acid, phenylethyl ester (CAPE) and curcumin inhibit by modification of gating, not by blocking the pore (Choi et al. 2013). Potassium ions can inhibit tumorigenesis through inducing apoptosis of hepatoma cells by upregulating potassium ion transport channel proteins HERG and VDAC1 (Xia et al. 2016).  Incorrectly folded hERG can be degraded by Bag1-stimulated Trc-8-dependent proteolysis (Hantouche et al. 2016). The S1 helix regulates channel activity. Thus, S1 region mutations reduce both the action potential repolarizing current passed by Kv11.1 channels in cardiac myocytes, as well as the current passed in response to premature depolarizations that normally helps protect against the formation of ectopic beats (Phan et al. 2017). Interactions of beta1 integrins with hERG1 channels in cancer cells stimulate distinct signaling pathways that depended on the conformational state of hERG1 (Becchetti et al. 2017). ERG1 is sensitive to the alkaloid, ginsenoside 20(S) Rg3 which alters the gating of hERG1 channels by interacting with and stabilizing the voltage sensor domain in an activated state (Gardner et al. 2017). Channels split at the S4-S5 linker, at the intracellular S2-S3 loop, and at the extracellular S3-S4 loop are fully functional channel proteins (de la Peña et al. 2018). IKr is the rapidly activating component of the delayed rectifier potassium current, the ion current largely responsible for the repolarization of the cardiac action potential. Inherited forms of long QT syndrome (LQTS) in humans are linked to functional modifications in the Kv11.1 (hERG) ion channel and potentially life threatening arrhythmias. hERG1b affects the generation of the cardiac Ikr and plays an important role in cardiac electrophysiology (Perissinotti et al. 2018).

Animals (Mammals)

H-ERG of Homo sapiens (Q12809)

 
1.A.1.20.2Erg2 (Kv11.2) K+ channel with slowly activating delayed rectifier (expressed only in the nervous system) (Shi et al., 1997)AnimalsErg2 of Rattus norvegicus
(O54853)
 
1.A.1.20.3

Erg3 (Kv11.3) K+ channel with a large transient current at positive potentials (expressed only in the nervous system) (Shi et al., 1997). Erg3-mediated suppression of neuronal intrinsic excitability prevents seizure generation (Xiao et al. 2018).

Animals

Erg3 of Rattus norvegicus
(O54852)

 
1.A.1.20.4

K+ voltage-gated channel, rEAG1; Kv10.1; rat ether a go-go channel 1 (962 aas). Blocked by Cs+, Ba2+ and quinidine (Schwarzer et al., 2008). Cysteines control the N- and C-linker-dependent gating of KCNH1 potassium channels  (Sahoo et al., 2012).  The 3-d structure has been determined at 3.8 Å resolution using single-particle cryo-EM with calmodulin bound. The structure suggests a novel mechanism of voltage-dependent gating. Calmodulin binding closes the potassium pore (Whicher and MacKinnon 2016). Eag1 has three intracellular domains: PAS, C-linker, and CNBHD. Whicher and MacKinnon 2019 demonstrated that the Eag1 intracellular domains are not required for voltage-dependent gating but likely interact with the VS to modulate gating. Specific interactions between the PAS, CNBHD, and VS domains modulate voltage-dependent gating, and VS movement destabilizes these interactions to promote channel opening. Mutations affecting these interactions render Eag1 insensitive to calmodulin inhibition (Whicher and MacKinnon 2019). The structure of the calmodulin insensitive mutant in a pre-open conformation suggests that channel opening may occur through a rotation of the intracellular domains, and calmodulin may prevent this rotation by stabilizing interactions between the VS and the other intracellular domains. Intracellular domains likely play a similar modulatory role in voltage-dependent gating of the related Kv11-12 channels.


Animals

EAG1 of Rattus norvegicus (Q63472)

 
1.A.1.20.5

Potassium voltage-gated channel subfamily H member 3 (Brain-specific eag-like channel 1) (BEC1) (Ether-a-go-go-like potassium channel 2) (ELK channel 2) (ELK2) (Voltage-gated potassium channel subunit Kv12.2). A selective inhibitor is ASP2905 (Takahashi et al. 2017).

Animals

KCNH3 of Homo sapiens

 
1.A.1.20.6

Cyclic nucleotide-binding, voltage-gated, Mg2+-dependent, CaMKII-regulated K+ channel, Eag.  Eag recruits CASK (TC# 9.B.106.3.2) to the plasma membrane; forms a heterotetramer (Liu et al. 2010).

Animals

Eag of Drosophila melanogaster

 
1.A.1.20.7

Cyclic nucleotide-gated K+ channel, CNGC or CNG1 of 894 aas and 6 TMSs (Wheeler and Brownlee 2008).

CNG1 of Chlamydomonas reinhardtii

 
1.A.1.20.8

Aureochrome 1-like protein of 370 aas and a probable C-terminal 2 TMS ion channel domain.

Aureochrome 1 of Chattonella antiqua

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.21.1

K+- and Na+-conducting NaK channel (3-D structure solves with Na+ and K+) (Shi et al., 2006).  Exhibits tight structural and dynamic coupling between the selectivity filter and the channel scaffold (Brettmann et al. 2015).

Bacteria

NaK channel of Bacillus cereus (2AHYB) (Q81HW2)

 
1.A.1.21.2

Two pore domain potassium channel family protein of 122 aas and 2 TMSs.

K+ channel of Anaerolineales bacterium

 
1.A.1.21.3

Two pore domain potassium channel family protein of 140 aas and 2 TMSs.

K+ channel of Methanosarcina mazei

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.22.1The cyclic nucleotide-gated K+ channel, MmaK. (Activated by cyclic AMP and cyclic GMP; inactivated at slightly acidic pH (Kuo et al., 2007))Gram-negative bacteria MmaK of Magnetospirillum magnetotacticum (Q2W0I8)
 
Examples:

TC#NameOrganismal TypeExample
1.A.1.23.1

The pea symbiosis protein, essential for nodulation, mycorrhization, and Nod-factor-induced calcium spiking, SYM8 or DMI1 (Does not make infections 1). (Most similar to 1.A.1.13.2; 894aas; 4 TMSs between residues 136 and 339) (Edwards et al., 2007).

Plants

SYM8 of Pisum sativum
(Q4VY51)

 
1.A.1.23.2Root nuclear envelope CASTOR: homomeric ion channel (preference of cations such as K+ over anions) (Charpentier et al., 2008) (62% identical to 1.A.1.23.1).

Plants

CASTOR of Lotus japonicus (Q5H8A6)

 
1.A.1.23.3POLLUX homomeric ion channel (preference for cations over anions) (Charpentier et al., 2008) (81% identical to 1.A.1.23.1).

Plants

POLLUX of Lotus japonicus (Q5H8A5)

 
1.A.1.23.4

putative ion channel (N-terminal domain) protein with C-terminal TrkA-N domain (DUF1012); NAD-binding lipoprotein.

Actinobacteria

Ion channel protein of Streptomyces coelicolor

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.24.1The cyclic nucleotide regulated K+ channel, CNR-K+ channel (412 aas)BacteriaCNR-K+ channel of Rhodopseudomonas palustris (Q02006)
 
1.A.1.24.2

K+ channel protein homologue 

δ-Proteobacteria

K+ channels protein homologue of Stigmatella aurantiaca (Q08U57)

 
1.A.1.24.3

Putative 6 TMS potassium channel

Proteobacteria

Potassium ion channel of Myxococcus xanthus

 
1.A.1.24.4

Putative K+ channel

Cyanobacteria

K channel of Cyanotheca (Synechococcus) sp PCC8801

 
1.A.1.24.5

Cyclic nucleotide-gated K+ channel of 459 aas.

Proteobacteria

Channel of Labenzia aggregata

 
1.A.1.24.6

Uncharacterized ion channel protein of 276 aas and 6 TMSs

UP of Flavobacterium psychrolimnae

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.25.1

The 6TMS bacterial cyclic nucleotide-regulated, voltage independent channel, MlotiK1 or MloK1 (Clayton et al., 2008). Gating involves large rearrangements of the cyclic nucleotide-binding domains (Mari et al., 2011).  The electron crystalographic structure is available (PDB 4CHW)revealing ligand-induced structural changes (Schünke et al. 2011; Scherer et al. 2014; Kowal et al. 2014). Such changes may be lipid dependent (McCoy et al. 2014).

Bacteria

MlotiK1 of Mesorhizobium loti (Q98GN8)

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.26.1The rodent malaria parasite K+ channel, PfKch1 (929aas) (Ellekvist et al., 2008).EukaryotesKch1 of Plasmodium berghei (Q4YNK7)
 
Examples:

TC#NameOrganismal TypeExample
1.A.1.27.1

Putative 4 TMS ion channel protein.  TMSs 1-2 may not be homologous to TMSs 3-4 which probably form the channel.

Actinomycetes

Hypothetic VIC family member of Streptomyces coelicolor

 
1.A.1.27.2

Putative 4 TMS potassium ion channel protein.  TMSs 1-2 may not be homologous to TMSs 3-4 which probably form the channel.

Actinobacteria

Putative ion channel of Streptomyces coelicolor

 
1.A.1.27.3

Uncharacterized protein of 114 aas

Proteobacteria

UP of Rhizobium meliloti

 
1.A.1.27.4

Uncharacterized protein of 148 aas and 3 or 4 TMSs

UP of Marinobacter hydrocarbonoclasticus

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.28.1

Putative K+ channel

Proteobacteria

Putative K+ channel of Klebsiella varicola (D3RJS6)

 
1.A.1.28.2

Putative K+ channel

Proteobacteria

Putative K+ channel of Pseudomonas fluorescens (C3K1P0) 

 
1.A.1.28.3

Thylakoid membrane 6 TMS voltage-sensitive K+ channel, SnyK; important for photosynthesis (Checchetto et al. 2012).

Cyanobacteria

SynK of Synechocystis sp.

 
1.A.1.28.4

Putative voltage-dependent K+ channel

γ-Proteobacteria

K+ channel of Vibrio alginolytcus

 
1.A.1.28.5

Putative voltage-dependent K+ channel

γ-Proteobacteria

K+ channel of E. coli

 
1.A.1.28.6

Putative voltage-dependent K+ channel

Proteobacteria

K+ channel of Acinetobacter baumannii

 
1.A.1.28.7

Uncharacterized protein of 228 aas and 6 TMSs

UP of Methanoculleus bourgensis (Methanogenium bourgense)

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.29.1

The 2 - 4 TMS K+ channel, LctB (Wolters et al. 1999).

Gram-positive bacteria

LctB of Bacillus stearothermophilus

 
1.A.1.29.2

Uncharacterized protein of 481 aas and 2 TMSs.  (Pfam CL0030)

Euryarchaeota

UP of Pyrococcus furiosus

 
1.A.1.29.3

Uncharacterized protein of 326 aas and 2 TMSs

UP of Pseudoalteromonas luteoviolacea

 
1.A.1.29.4

C-terminal 2 TMS channel protein of 723 aas with 5 N-terminal pentapeptide repeats in a YjbI domain of unknown function

Channel protein of Natrinema altunense

 
1.A.1.29.5

Ion transport 2 domain-containing protein of 345 aas and 2 TMSs

Ion transport 2 domain-containing protein of Halococcus salifodinae

 
1.A.1.29.6

Putative cation transporting channel-2 of 288 aas with 2 N-terminal TMSs (Hug et al. 2016).

Channel-2 of Candidatus Peribacter riflensis

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.3.1

Large conductance, voltage- and Ca2+-activated K+ calcium-dependent potassium (BK) channel. Four pairs of RCK1 and RICK2 domains form the Ca2+-sensing apparatus known as the "gating ring" in Big Potassium (BK) channel proteins (Savalli et al., 2012). Gating of BK channels does not seem to require a physical gate. Instead, changes in the pore shape and surface hydrophobicity in the Ca2+-free state allow the channel to readily undergo hydrophobic dewetting transitions, giving rise to a large free energy barrier for K+ permeation (Jia et al. 2018).  Voltage-dependent dynamics of the BK channel cytosolic gating ring are coupled to the membrane-embedded voltage sensor (Miranda et al. 2018).

Animals

Ca2+-activated K+ channel of Drosophila melanogaster

 
1.A.1.3.2

Large conductance Ca2+ - and voltage-activated K+ channel, α-subunit (subunit α1), BK, BKCa, Kca1.1, Slowpoke, Slo1, KCNMA1 or MaxiK (functions with four β-subunits (TC# 8.A.14) encoded by genes KCNMB1-4 and the γ subunit (TC# 8.A.43) in humans (Toro et al. 2013; Li et al. 2016); the positions of beta2 and beta3 have been determined (Wu et al. 2013).  The KB channel is inhibited by 3 scorpion toxins, charybda toxin, iberiotoxin and slotoxin.  It forms a ''Ca2+  nanodomain'' complex with Cav1.2 (L-type; 1.A.1.11.4), Cav2.1 (P/Q-type; 1.A.1.11.5) and Cav2.2 (N-type; 1.A.1.11.6) where Ca2+ influx through the Cav channel activates BKCa (Berkefeld et al., 2006; Romanenko et al., 2006). The RCK2 domain is a Ca2+ sensor (Yusifov et al., 2008). Binding of Ca2+ to D367 and E535 changes the conformation around the binding site and turns the side chain of M513 into a hydrophobic core, explaining how Ca2+ binding opens the activation gate of the channel (Zhang et al., 2010). A structural motif in the C-terminal tail of Slo1 confers carbon monoxide sensitivity to human BKCa channels (Williams et al., 2008; Hou et al., 2008). These channels are present in the inner mitochondrial membrane of rat brain (Douglas et al., 2006).The Stress-Axis Regulated Exon (STREX) is responsible for stretch sensitivity. Ca2+ binds to two sites. Ca2+ binding to the RCK1 site is voltage dependent, but Ca2+ binding to the Ca2+ bowl is not (Sweet and Cox et al., 2008). Type 1 IP3 receptors activate BKCa channels via local molecular coupling in arterial smooth muscle cells (Zhao et al., 2010). The open structure is known (Yuan et al., 2012). BKCa is essential for ER calcium uptake in neurons and cardiomyocytes (Kuum et al., 2012) and link Ca2+ signaling to action potential firing and neurotransmitter release via serotonin receptors in many types of neurons (Rothberg 2012). The molecular mechanism of pharmacological activation of BK channels has been discussed by Gessner et al. (2012). The first TMS of the β2-subunit binds to TMS S1 of the α-subunit (Morera et al., 2012).  Mutations in Cav1.2 give rise to Timothy syndrome (Dixon et al. 2012).  Exhibits low voltage activation by interaction with Cav3 (Rehak et al. 2013) as well as Ca2+-gating (Berkefeld and Fakler 2013). Single-channel kinetics have been reported (Geng and Magleby 2014). The γ-subunit has TC# 8.A.43.1.8.  RBK channels regulate myogenesis in vascular smooth muscle cells (Krishnamoorthy-Natarajan and Koide 2016). Latorre et al. 2017 reviewed molecular, physiological and pathological aspects of Slo1. The microRNA, mmumiR449a, reduced the mRNA expression levels of transient receptor potential cation channel subfamily A member 1 (TRPA1), and calcium activated potassium channel subunit alpha1 (KCNMA1) and increased the level of transmembrane phosphatase with tension homology (TPTE) in the DRG cells (Lu et al. 2017), thereby reducing pain. The N-terminal sequence determines its modification by β-subunits (Lorca et al. 2017). Inhibition of BKCa negatively alters cardiovascular function (Patel et al. 2018). BKCa may be the target of verteporfin, a benzoporphyrin photosensitizer that alters membrane ionic currents (Huang et al. 2019).

Animals

BKCa or MaxiK channel of Rattus norvegicus (Q62976)

 
1.A.1.3.3

Ca2+-activated K+ channel Slo-1 (Maxi K; BK channel) (ethanol-activated; responsible for intoxication) (Davies et al., 2003); tyrosyl phosphorylation regulates BK channels via cortactin (Tian et al. 2008a), but palmitoylation gates phosphorylation-dependent regulation of BK potassium channels (Tian et al., 2008b). Also regulated by Mg2+ which mediates interaction between the voltage sensor and cytosolic domain to activate BK channels (Yang et al., 2007). Modulated by the ss2 subunit (Lee et al., 2010). The structure of the gating ring from the human large-conductance Ca2+-gated K+ channel has been reported (Wu et al., 2010). Four pairs of RCK1 and RICK2 domains form the Ca2+-sensing apparatus known as the "gating ring" in BK channel proteins (Savalli et al., 2012).  The dystrophin (Q9TW65) dystrobrevin (Q9Y048) complex controls BK channel localization and muscle activity as well as neurotroansmitter release (Kim et al. 2009, Chen et al. 2011).  Syntrophin (Q93646) links various receptors and transporters to the actin cytoskeleton and the dystrophin glycoprotein complex (DGC), and α-catulin (CTN-1; 759 aas, 0 TMSs) facilitates targeting.

Animals

BK K+ channel of Caenorhabditis elegans (Q95V25)

 
1.A.1.3.4

The one or two component intracellularly Na+ and Cl--activated delayed rectifier K+ channel, rSlo2.2 (Slack; KCNT1)/r Slo2.1 (Slick; KCNT2; TC# 1.A.1.3.6) provides protection against ischemia (Yuan et al., 2003). The N-terminal domain of Slack determines the formation and trafficking of Slick/Slack heteromeric sodium-activated potassium channels (Chen et al., 2009). Slick and Slack can also form separate homooligomeric channels. These channels are widely distributed in the mammalian CNS and they play roles in slow afterhyperpolarization, generation of depolarizing afterpotentials and in setting and stabilizing the resting potential (Rizzi et al. 2015). The small cytoplasmic protein beta-synuclein TC# 1.C.77.1.2) and the transmembrane protein 263 (TMEM 263; TC# 8.A.101.1.1) are interaction partners of both Slick and Slack channels. The inactive dipeptidyl-peptidase (DPP 10) and the synapse associated protein 102 (SAP 102) are constituents of the Slick and Slack channel complexes (Rizzi et al. 2015).

Animals

Slo2 of Rattus norvegicus (Q9Z258)

 
1.A.1.3.5

Sperm Slo3 high conductance K+ channel, activated by voltage and intracellular alkalinization. In sperm, it gives rise to pH-dependent outwardly rectifying K+ currents. (required for the ensuing acrosome reaction; activated by phosphatidylinositol 4,5-bisphosphate (PIP(2)) (Tang et al., 2010).

Animals

Slo3 of Mus musculus (O54982)

 
1.A.1.3.6

Human outward rectifying potassium channel, Slo2.1 (also called KCNT2 and Slick) of 1135 aas. Produces rapidly activating outward rectifier K+ currents. Activated by high intracellular sodium and chloride levels. Channel activity is inhibited by ATP and by inhalation of anesthetics such as isofluraneInhibited upon stimulation of G-protein coupled receptors such as CHRM1 and GRIA1.  Orthologous to 1.A.1.3.4 (Garg et al. 2013) and can form a heteromeric complex with it and several other proteins (see TC# 1.A.1.3.4).  Hydrophobic interactions between residues in S5 and the C-terminal end of the pore helix stabilize Slo2.1 channels in a closed state (Suzuki et al. 2016).

Animals

Slo2.1 of Homo sapiens

 
1.A.1.3.7

Slo2.2 sodium-activated potassium channel subfamily T member 1 of 1217 aas and 6 putative N-terminal TMSs plus a P-loop.  Cryo electron microscopic structures of the chicken orthologue at 4.5 Å resolution has been solved, revealing a large cytoplasmic gating ring in which resides the Na+-binding site and a transmembrane domain that closely resembles voltage-gated K+ channels (Hite et al. 2015).

Slo2.2 of Homo sapiens

 
1.A.1.3.8

SLOwpoke K+ channel, SLO-2 or Slo2, of 1107 aas and 6 TMSs, present in motor neurons.  It has six putative TMSs with a K+-selective pore and a large C-terminal cytosolic domain (Lim et al. 1999). Its requirements for both Cl- and Ca2+ are synergistic and associated with the same functional domain (Yuan et al. 2000) which serves to counteract hypoxia stress when cytoplasmic Cl- and Ca2+ concentrations increase (Yuan et al. 2003; Santi et al. 2003).  SLO2 protects from hypoxic injury by increasing the permeability of the mitochondrial inner membrane to K+ (Wojtovich et al. 2011). SLO-2 is functionally coupled with CaV1 and regulates neurotransmitter release (Liu et al. 2014).  Partially responsible for action potential repolarization during synaptic transmission (Ford and Davis 2014).

Slo-2 of Caenorhabditis elegans

 
1.A.1.3.9

Voltage-gated calcium-activated potassium channel of 862 aas and 6 or 7 TMSs.

VIC protein of Entamoeba histolytica

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.30.1

Uncharacterized putative chloride channel protein of 219 aas and 2 TMSs.

UP of Vibrio phage 1.081.O._10N.286.52.C2

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.31.1

Uncharacterized VIC superfamily member of 230 aas and 6 or 7 TMSs (Anwar and Samudrala 2018).

UP of Entamoeba histolytica

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.4.1

K+ channel, AKT1; may form heteromeric channels with KC1 (TC # 1.A.1.4.9) (Geiger et al., 2009).  Required for seed development and postgermination growth in low potassium (Pyo et al. 2010).  Functions optimally with intermediate potassium concentrations (~1 mM) (Nieves-Cordones et al. 2014).

Plants

AKT1 of Arabidopsis thaliana

 
1.A.1.4.10Inward rectifier K+ channel AKT1 (45% identical to 1.A.1.4.1; 944aas) (Garciadeblas et al., 2007).

Mosses

Akt1 of Physcomitrella patens (A5PH36)

 
1.A.1.4.11

Potassium channel, KCN11.  The UniProt entry included here is not complete. The correct gene ID is Cre06.g278111 in the Chlamydomonas genome database Phytozome. The complete sequence and description of its function are published by Xu et al. (2016).  KCN11 is a 6 TMS organelle K+ channel found exclusively in the contractile vacuole. It is required for osmoregulation under hypotonic conditions (Xu et al. 2016).

KCN11 of Chlamydomonas reinhardtii (Chlamydomonas smithii)

 
1.A.1.4.12

Synthetic light-sensitive K+ channel, BLINK2, of 406 aas and 2 TMSs with a P-loop between the two TMSs (residues 158 - 233). Residues 8 - 142 are derived from residues 403 - 537 of NPH1-1, a light-sensitive ser/thr protein kinase of the oat plant, Avena sativa ( acc # AAC05083); residues 143 - 234 are derived from residues 3 - 94 of the Paramecium bursaria Chlorella virus 1 (PBCV-1) K+ channel, Kcv1 (TC# 1.A.1.12.1); residues 235 - 404 derive from residues 506 - 675 of another K+ channel protein, KAT1 (TC# 1.A.1.12.1). BLINK1 has been used to manipulate stomatal kinetics to improve carbon assimilation, water use, and growth of A. thaliana (Papanatsiou et al. 2019).


Synthetic light-sensitive K+ channel, BLINK2.

 
1.A.1.4.2K+channel, KDC1 (voltage and pH-dependent; inward rectifying). Does not form homomeric channels. The C-terminus functions in the formation of heteromeric complexes with other potassium alpha-subunits such as KAT1 (1.A.1.4.7) (Naso et al., 2009).

Plants

KDC1 of Daucus carota

 
1.A.1.4.3Inward rectifying, pH-independent K+ channel, KZM1 (Philippar et al., 2003)PlantsKZM1 of Zea mays (CAD18901)
 
1.A.1.4.4

Guard cell outward rectifying K+ out channel, GORK, controls leaf stomatal pore opening (by increasing solute content) and closing (by decreasing solute content), which in turn controls gas and water loss (Schroeder, 2003).

Plants

GORK of Arabidopsis thaliana (CAC17380)

 
1.A.1.4.5

Root stelar K+ outward rectifying channel, SKOR (involved in K+ release into the xylem sap; part of the plant water stress response) (Gaymard et al., 1998). SKOR is an outwardly rectifying K+ channel that mediates the delivery of K+ from stelar cells to the xylem in the roots, a critical step in the long-distance distribution of K+ from roots to the upper parts of the plant. Liu et al. 2006 and Johansson et al. 2006 reported that SKOR channel activity is strictly dependent on intracellular and extracellular K+ concentrations. Activation by K+ did not affect the kinetics of voltage dependence, indicating that a voltage-independent gating mechanism underlies K+ sensing. The C-terminal non-transmembrane region is required for sensing. The intracellular K+ sensing mechanism couples SKOR activity to the K+ status of the 'source cells', thereby establishing a supply-based unloading system for the regulation of K+ distribution (Liu et al. 2006; Johansson et al. 2006).

Plants

SKOR of Arabidopsis thaliana (AAF26975)

 
1.A.1.4.6

Heterotetrameric K+ channel, KAT2/AKT2/KCT2 (Nieves-Cordones et al. 2014). Forms heteromeric channels (2:2 stoichiometry) with KAT1 (1.A.1.4.7) (Lebaudy et al., 2010) (Properties differ from those of homomeric channels; Xicluna et al., 2007).  KAT2 also forms homomeric channels in the plasma membrane (Nieves-Cordones et al. 2014). AKT2 functions in phloem loading and unloading and operates as an inward-rectifying channel that allows H+-ATPase-energized K+ uptake. Through reversible post-translational modifications, it can also function as an open, K+-selective channel, providing energy for transmembrane transport processes. It is present in a complex of several proteins in which it interacts with the receptor-like kinase, MRH1/MDIS2 (Sklodowski et al. 2017). The ortholog in Brassica rapa (Chinese cabbage), KCT2, is induced by stress. It has a TxxTxGYGD motif in the P-domain and a putative cyclic nucleotide-binding-like domain within a long C-terminal region (Zhang et al. 2006).

 

Plants

AKT2/KAT2 of Arabidopsis thaliana
AKT2 (Q38898)
KAT2 (Q38849)

 
1.A.1.4.7

The voltage-sensitive inward rectifying K+ channel, KAT1 (similar to 1.A.1.4.3; activated by protein 14-3-3 (AAF87262)) (Sottocornola et al., 2006). May also transport Na+ and Cs+ (Nakamura and Gaber, 2009). Forms heterotetrameric channels with KAT2 with a stoichiometry of 2:2 (Lebaudy et al., 2010). The pH-sensor is built of a sensory cloud rather than of single key amino acids (Gonzalez et al., 2011). The transmembrane core region of KAT1 is important for its activity in S. cerevisiae, and this involves not only the pore region but also parts of its voltage-sensor domain (Saito et al. 2017).

Plants

KAT1 of Arabidopsis thaliana (Q39128)

 
1.A.1.4.8Inward rectifying Shaker K+ channel SPIK (AKT6) (expressed in pollen, and involved in pollen tube development) (Mouline et al., 2002). PlantsSPIK of Arabidopsis thaliana
(Q8GXE6)
 
1.A.1.4.9

The KC1 (KAT3) potassium channel-like subunit; regulates other channels such as AKT1 (1.A.1.4.1) and KAT1 (1.A.1.4.7) (Duby et al., 2008); may form heteromeric channels with AKT1 (Geiger et al., 2009). It forms a tripartite SNARE-K+ channel complex which regulates KAT3 channel opening (Honsbein et al., 2009).  Tripartite interactions with SNARE (SYP121; SYR1; PEN1) and AKT1 control gating (Grefen et al. 2010).  ZKC1 also forms homoleric channels in the endoplasmic reticulum (Nieves-Cordones et al. 2014).

Plants

KC1 of Arabidopsis thaliana (P92960)

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.5.1Cyclic nucleotide-gated (CNG) nonselective cation channel (PNa+ /PK+ ≈ 1.0)AnimalsCNG channel of Ictalurus punctatus
 
1.A.1.5.10

Orthologue K+/Na+ pacemaker channel, Hcn4 (Scicchitano et al., 2012).  Hyperpolarization-activated cyclic nucleotide-regulated HCN channels underlie the Na+-K+ permeable IH pacemaker current. As with other voltage-gated members of the 6-transmembrane KV channel superfamily, opening of HCN channels involves dilation of a helical bundle formed by the intracellular ends of S6, but this is promoted by inward, not outward, displacement of S4. Direct agonist binding to a ring of cyclic nucleotide-binding sites, one of which lies immediately distal to each S6 helix, imparts cAMP sensitivity to HCN channel opening. At depolarized potentials, HCN channels are further modulated by intracellular Mg2+ which blocks the open channel pore and blunts the inhibitory effect of outward K+ flux. Lyashchenko et al. 2014 showed that cAMP binding to the gating ring enhances not only channel opening but also the kinetics of Mg2+ block.  Mutations in HCN4 cause sick sinus and the Brugada syndrome, cardiac abnormalities. Associated withfamiial sinus bradycardia (Boulton et al. 2017).

Animals

Hcn4 of Homo sapiens (Q9Y3Q4)

 
1.A.1.5.11

Hyperpolarization-activated cyclic nucleotide-gated (HCN) inward current carrying cationic channel, I(f), (HCN2/HCN4) (Ye and Nerbonne, 2009).

Animals

HCN2/HCN4 channels of Homo sapiens 
HCN2 (Q9UL51)
HCN4 (Q9Y3Q4) 

 
1.A.1.5.12

Cyclic nucleotide-gated cation channel α3 (CNGA3 or CNG3); photoreceptor cGMP-gated channel α-subunit. Also possibly expressed in inner ear cell cells where it binds to an intracellular C-terminal domain of EMILIN1 (Selvakumar et al., 2012).  Elastic network model analysis of the CNGA3 channel supports a modular model of allosteric gating, according to which protein domains are quasi-independent: they can move independently but are coupled to each other allosterically (Gofman et al. 2014).

Animals

CNGA3 of Homo sapiens (Q16281) 

 
1.A.1.5.13

Trout cyclic nucleotide-gated cation channel α3 (CNGA3 or CNG3). Expressed in inner ear cell cells where it binds to an intracellular C-terminus domain of EMILIN1 (Selvakumar et al., 2012). 

Animals

CNGA3 of Oncorhynchus mykiss (G9BHJ0)

 
1.A.1.5.14Probable cyclic nucleotide-gated ion channel 6 (AtCNGC6) (Cyclic nucleotide- and calmodulin-regulated ion channel 6)PlantsCNGC6 of Arabidopsis thaliana
 
1.A.1.5.15

Cyclic nucleotide gated K+ channel of 650 aas

Amoebae

Channel of Naegleria gruberi

 
1.A.1.5.16

Cyanobacterial cyclic nuceotide K+ channel of 454 aas (Brams et al. 2014).

Cyanobacteria

Channel of Trichodesmium erythraeum

 
1.A.1.5.17

Cyclic nucleotide-gated K+channel of 430 aas.  Activated by cAMP, not by cGMP.  Highly specific for K+ over Na+.  Has a C-terminal cAMP-binding domain linked to the 6 TMS channel domain (Brams et al. 2014).

Spirochaetes

Channel of Spirochaeta thermophila

 
1.A.1.5.18

Cyclic nucleotide-gated cation (CNG) channel of 665 aas.

Animals (Insects)

CNG of Drosophila melanogaster

 
1.A.1.5.19

TAX-2 cyclic nucleotide-gated cation channel-B (CNGB) of 800 aas (Wojtyniak et al. 2013).

Animals

TAX-2 CNGB of Caenorhabditis elegans

 
1.A.1.5.2

Hyperpolarization-activated and cyclic nucleotide-gated K+ channel, HCN (bCNG-1) (PNa+/PK+ ≈ 0.3). The human orthologue (O88703) is 863 aas in length and also catalyzes mixed monovalent cation currents K+:Na+= 4:1 (Lyashchenko and Tibbs et al., 2008). Biel et al. (2009) presented a detailed review of hyperpolarization-activated cation-channels. They are inhibited by nicotine and epibatidine which bind to the inner pore (Griguoli et al., 2010). They control cardiac and neuronal rhythmicity. HCN channels contain cyclic nucleotide-binding domains (CNBDs) in their C-terminal regions, linked to the pore-forming transmembrane segment with a C-linker. The C-linker couples the conformational changes caused by the direct binding of cyclic nucleotides to the HCN pore opening. Cyclic dinucleotides antagonize the effect of cyclic nucleotides in HCN4 but not in HCN2 channels. Interaction of the C-linker/CNBD with other parts of the channel appears to be necessary for cyclic-dinucleotide binding in HCN4 channels (Hayoz et al. 2017).

Animals

HCN of Mus musculus

 
1.A.1.5.20

TAX-4 cyclic nucleotide-gated cation channel A (CNGA) of 733 aas (Wojtyniak et al. 2013).  Li et al. 2017 determined the 3.5 Å resolution single-particle electron cryo-microscopy structure  in the cyclic guanosine monophosphate (cGMP)-bound open state. The channel has an unusual voltage-sensor-like domain, accounting for its deficient voltage dependence. A carboxy-terminal linker connecting S6 and the cyclic-nucleotide-binding domain interacts directly with both the voltage sensor-like domain and the pore domain, forming a gating ring that couples conformational changes triggered by cyclic nucleotide binding to the gate. The selectivity filter is lined by the carboxylate side chain of a functionally important glutamate and three rings of backbone carbonyls (Li et al. 2017).

Animals

TAX-4 CNGA of Caenorhabditis elegans

 
1.A.1.5.21

K+ channel protein, PAK2.1 of 543 aas.  Contains a cyclic nucleotide-binding domain (Ling et al. 1998; Jegla and Salkoff 1995).

Alveolata (ciliates)

PAK2.1 of Paramecium tetraurelia

 
1.A.1.5.22

K+ channel protein, PAK11-MAC of 772 aas.  Contains a cyclic nucleotide-binding domain (Ling et al. 1998; Jegla and Salkoff 1995).

Alveolata (ciliates)

PAK11-MAC of Paramecium tetraurleia

 
1.A.1.5.23

Cyclic nuceotide-gated Na+ channel of 729 aas and 6 putative TMSs, CNGC19.  Constitutively expressed in roots but Induced in leaves and shoots under conditions of salt (NaCl) stress (Kugler et al. 2009).

CNGC19 of Arabidopsis thaliana

 
1.A.1.5.24

Cyclic nucleotide-gated Na+ channel of 764 aas and 6 putative TMSs, CNGC20.  Induced in shoots in response to salt (NaCl) stress (Kugler et al. 2009).

CNGC20 of Arabidopsis thaliana

 
1.A.1.5.25

Putative cyclic AMP receptor protein (Crp), annotated in GenBank as a Crp homologue with a CAP_ED domain N-terminal and a helix-turn-hexix (HTH) domain C-terminal. This protein has two poorly hydrophobic peaks at ~ residue # 85 and 165, with a potential "P-loop" between these two peaks.  All of the cyclic nucleotide regulated channels in subfamily 2.A.1.5 have the two TMSs separated by about 80 residues with the P-loop inbetween.  Maybe the cAMP binding domains in the transcription factors and the channel proteins are derived from a common origin, and are therefore homologous.

Putative Crp homologue of Bifidobacterium longum

 
1.A.1.5.26

Cyclic nuceotide gated channel of 706 aas, CNGC18.  It is the essential Ca2+ channel for pollen tube guidance (Gao et al. 2016).

CNGC18 of Arabidopsis thaliana (Mouse-ear cress)

 
1.A.1.5.27

CNGC15 of 678 aas and 6 TMSs.  In Medicago truncatula, three such channels, CNGC15a, b and c, are required for nuclear calcium oscillations, spiking and subsequent symbiotic responses. These three channels form a complex with the potassium permeable channel, DMI1 (TC# 1.A.1.23.1), in the nuclear envelope.  They are expressed in flowers and pods, and mutants in these channels have decreased fertilization rates (Charpentier et al. 2016). 

CNG15 of Arabidopsis thaliana

 
1.A.1.5.28

The cyclic nucleotide-gated cation channel, CNG-1 of 661 aas and 6 TMSs. CNG-1 functions in multiple capacities to link nutritional information with behavioral output (He et al. 2016).

CNG-1 of Caenorhabditis elegans

 
1.A.1.5.29

spHCN1 is a hyperpolarization-activated cyclic nucleotide-gated (HCN) non-selective cation channel of 767 aas and 6 TMSs that opens due to inward movement of the positive charges in the fourth transmembrane domain (S4).  These channels open after only two S4s have moved, and S4 motion is rate limiting during voltage activation of spHCN channels (Bruening-Wright et al. 2007). HCN channels regulate electrical activity in the heart and brain. Distinct from mammalian isoforms, the sea urchin (spHCN) channel exhibits strong voltage-dependent inactivation in the absence of cAMP (Idikuda et al. 2018). The voltage sensor undergoes a large downward motion during hyperpolarization (Dai et al. 2019).

	

HPN1 of Strongylocentrotus purpuratus (Purple sea urchin)

 
1.A.1.5.3

Heterotetrameric (3A:1B) rod photoreceptor cyclic GMP-gated cation channel, CNGA1 (Zhong et al., 2002). Cyclic nucleotides are required to open the channel. Gating is proposed to be initiated by an anticlockwise rotation of the N-terminal region of the C-linker, which is then, transmitted through the S6 transmembrane helices to the P-helix, and in turn from this to the pore lumen, which opens from 2 to 5Å, thus allowing for ion permeation (Giorgetti et al. 2005). Defects produce channelopathies (Biel & Michalakis, 2007). A ring of four Glutamate residues (Glu363) in the outer vestibule, and a ring of four Threonines (Thr360) in the inner vestibule of the pore of CNGA1 channels constitute binding sites for permeating ions (Marchesi et al., 2012).  The tetraspanning peripherin-2 (TC# 8.A.40.1.2) links rhodopsin to this cyclic nucleotide-dependent channel in the outer segments of rod photoreceptors.  The G266D retinitis pigmentosa mutation in TMS4 of rhodopsin abolishes binding of peripherin-2 and prevents association with the CNGA1/CNGB1a subunits present in the complex (Becirovic et al. 2014).  External protons cause inactivation (Marchesi et al. 2015). CNG transmembrane domains have dynamic structure, undergoing conformational rearrangements (Maity et al. 2015).  Moreover, structural heterogeneity of CNGA1 channels has been demonstrated (Maity et al. 2016).

Animals

CNG of Homo sapiens
Subunit A1 (CNGA1)
Subunit B1 (CNGB1)

 
1.A.1.5.30

Hyperpolarization-activated cyclic nucleotide-modulated cation channel splice variant ABs-II of 682 aas and probably 6 TMSs, Ih channel encoded by the PIIH gene (Ouyang et al. 2007). 

Ih channel of Panulirus interruptus (California spiny lobster) (Palinurus interruptus)

 
1.A.1.5.31

Multi-domain cation channel with a C-terminal cyclic nucleotide-binding domain; of 465 aas and 6 TMS, LliK.  Cyclic nucleotide-gated (CNG) and hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels play roles in phototransduction, olfaction, and cardiac pace making.  James et al. 2017 used cryoEM to determine the structure of the intact LliK CNG channel. A short S4-S5 linker connects voltage-sensing and pore domains to produce a non-domain-swapped transmembrane architecture. The conformation of the LliK structure may represent a functional state of this channel family not seen before (James et al. 2017).

LliK of Leptospira licerasiae

 
1.A.1.5.32

HCN1 is a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel of 890 aas and 6 TMSs that opens due to inward movement of the positive charges in the fourth transmembrane domain (S4).  These channels open after only two S4s have moved, and S4 motion is rate limiting during voltage activation of spHCN channels (Bruening-Wright et al. 2007). HCN1 exhibits weak selectivity for potassium over sodium ions.  It's structure (3.5 Å resolution) is known (Lee and MacKinnon 2017).  It contributes to the native pacemaker currents in heart and neurons. It may also mediate responses to sour stimuli. It is inhibited by Cs+, zatebradine, capsazepine and ZD7288 (Gill et al. 2004). HCN1 mutational variants include epileptic encephalopathy and common generalized epilepsy. HCN1 has a pivotal function in brain development and control of neuronal excitability (Marini et al. 2018).

 

HCN1 of Homo sapiens

 
1.A.1.5.33

Hyperpolarization-gated and cyclic nucleotide regulated K+ channel of 638 aas and 6 TMSs, HCN2, present in the flagellum of sea urchin sperm (Galindo et al. 2005)

HCN2 of Strongylocentrotus purpuratus (Purple sea urchin)

 
1.A.1.5.4Olfactory heteromeric cyclic nucleotide-gated cation (mainly Na+, Ca2+) channel CNGA2/CNGA4/CNGB1b (present in sensory cilia of olfactory receptor neurons; activated by odorant-induced increases in cAMP concentration) (Michalakis et al., 2006).AnimalsCNGA2 complex of Mus musculus
CNGA2 (Q62398)
CNGA4 (AAI07349)
CNGB1b (NP_001288)
 
1.A.1.5.5

The cyclic nucleotide- and voltage-gated ion (K+, Rb+, Cs+) channel, CNGC1 (inward rectifying) (functions in heavy metal and cation transport, as does CNGC10) (Dreyer and Uozumi, 2011; Zelman et al., 2012).

Plants

CNGC1 of Arabidopsis thaliana (O65717)

 
1.A.1.5.6

The cyclic nucleotide-gated ion (K+, Rb+, Cs+) channel, CNGC2 (functions in plant defense responses, as does CNGC4) (Zelman et al., 2012).

Plants

CNGC2 of Arabidopsis thaliana (O65718)

 
1.A.1.5.7

The cyclic nucleotide-gated ion (K+, Rb+, Cs+) channel, HLM1 (CNGC4) (mediates the hypersensitive response (HR) of plants in programmed cell death.) Mutants show abnormal cell death and resistance to infection by Pseudomonas syringae (Balagué et al., 2003; Zelman et al., 2012).

Plants

HLM1 of Arabidopsis thaliana
(Q94AS9)

 
1.A.1.5.8

The non-selective cation transporter involved in germination, CNGC3 (Gobert et al., 2006; Zelman et al., 2012).

Plants

CNG3 of Arabidopsis thaliana (Q9SKD7)

 
1.A.1.5.9The cyclic nucleotide-gated K+ channel, Sp-tetraKCNG (2238 aas) (Galindo et al., 2007)AnimalsSp-tetraKCNG of Strongylocentrotus purpuratus (ABN14774)
 
Examples:

TC#NameOrganismal TypeExample
1.A.1.6.1

K+ channel, MthK or MVP of 209 aas and 6 TMSs.  Voltage-gated potassium-selective channel opened by hyperpolarization (Hellmer and Zeilinger 2003).  Mediates K+ uptake and sensitivity.  The structure and local dynamics of the closed activation gate (lower S6 region) of MVP have been reported (Randich et al. 2014).

Archaea

MthK channel protein of Methanocaldococcus jannaschii (Methanococcus jannaschii)

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.7.1

Tok1 twin (dual) barrel outward rectifying K+ channel with exterme assymmetry which includes an extra 4 N-terminal TMSs for a total of 16 TMSs.  (Transports K+ and Cs+) (Bertl et al., 2003; Roller et al. 2008).

Yeast

Tok1 outward rectifier K+ channel of Saccharomyces cerevisiae

 
1.A.1.7.2

AtTPK4 two-pore K+ channel 4 (Becker et al., 2004). Asp86 and Asp200 are essential for K+ permeation as well as inward rectification (Marcel et al., 2010).  Reviewed by González et al. 2014.

Plants

AtTPK4 of Arabidopsis thaliana (AAP82009)

 
1.A.1.7.3

The 2-pore (4TMS) outward rectifying K+ channel, KCO1 or TPK1. Possesses two tandem Ca2+-binding EF-hand motifs, and cytosolic free Ca2+ (~300 nM) activates (Czempinski et al., 1997).  Reviewed by González et al. 2014 and Basu and Haswell 2017.

Plants

KCO1 of Arabidopsis thaliana
(Q8LBL1)

 
1.A.1.7.4The two pore tonoplast TPK-type K+ channel; maintains K+ homeostasis in plant cells (Hamamoto et al., 2008); activated by 14-3-3 proteins (Latz et al., 2007).PlantsTPK1 of Nicotiniana tobacum (A9QMN9)
 
1.A.1.7.5

Two-pore potassium channel 5 (AtTPK5) (Calcium-activated outward-rectifying potassium channel 5, chloroplastic) (AtKCO5).  Reviewed by González et al. 2014.

Plants

TPK5 of Arabidopsis thaliana

 
1.A.1.7.6Potassium inward rectifier (Kir)-like channel 3 (AtKCO3)PlantsKCO3 of Arabidopsis thaliana
 
1.A.1.7.7

Chloroplast thylakoid two-pore calcium and proton-activated K+ channel, TPK3 of 436 aas and 4 TMSs.  Mediates ion counterbalancing, influencing photosynthetic llight utilization (Carraretto et al. 2013).  Reviewed by González et al. 2014.

Plants

TPK3 of Arabidopsis thaliana

 
1.A.1.7.8

Putative K+ channel of 96 aas nd 2 TMSs.

K+ channel of Yellowstone lake phycodnavirus 2

 
Examples:

TC#NameOrganismal TypeExample
1.A.1.8.1

TWIK-1 (KCNK1, HOHO1, KCNO1) inward rectifier K+ channel (Enyedi and Czirják, 2010) expressed in the distal nephron segments (Orias et al. 1997).  Lipid tails from both the upper and lower leaflets can partially penetrate into the pore (Aryal et al. 2015). The lipid tails do not sterically occlude the pore, but there is an inverse correlation between the presence of water within the hydrophobic barrier and the number of lipids tails within the lining of the pore (Aryal et al. 2015).

Mammals

TWIK-1 of Mus musculus

 
1.A.1.8.2

TASK-2 (KCNK5) two-pore domain, pH-sensitive, voltage-insensitive, outward rectifying K+ channel (K+ > Rb+ >> Cs+ > NH4+ > Na+ ≈ Li+), present in renal epithelia.  Regulated [inhibited] via group 1 metabolotropic glutamate receptors and by inositol phosphates (Chemin et al., 2003).  TASK-2 gating is controlled by changes in both extra- and intracellular pH through separate sensors: arginine 224 and lysine 245, located at the extra- and intracellular ends of transmembrane domain 4, respectively. TASK-2 is inhibited by a direct effect of CO2 and is regulated by and interacts with G protein subunits. TASK-2 takes part in regulatory adjustments and is a mediator in the chemoreception process in neurons of the retrotrapezoid nucleus where its pHi sensitivity could be important in regulating excitability and therefore signalling of the O2/CO2 status. Extracellular pH increases, brought about by HCO3- efflux from proximal tubule epithelial cells may couple to TASK-2 activation to maintain electrochemical gradients favourable to HCO3- reabsorption. TASK-2 is expressed at the basolateral membrane of proximal tubule cells (López-Cayuqueo et al. 2014). Mutations are associated with the Balkan Endemic Nephropathy (BEN) chronic tubulointerstitial renal disease (Reed et al. 2016). pH sensing in TASK2 channels is conferred by the combined action of several charged residues in the large extracellular M1-P1 loop (Morton et al. 2005).

 

Mammals

TASK-2 of Homo sapiens

 
1.A.1.8.3The 2P-domain K+ channel, TWIK 2 (functions in cell electrogenesis (Patel et al., 2000).AnimalsTWIK2 of Homo sapiens
(Q9Y257)
 
Examples:

TC#NameOrganismal TypeExample
Examples:

TC#NameOrganismal TypeExample
1.A.1.9.1

TREK-1 (KCNK2) K+ channel subunit (Regulated by group 1 metabotropic glutamate receptors and by diacylglycerols and phosphatidic acids) (Chemin et al., 2003). TREK-1, TREK-2 and TRAAK are all regulated by lysophosphatidic acid, converting these mechano-gated, pH voltage-sensitive channels into leak conductances (Chemin et al., 2005). The mammalian K2P2.1 potassium channel (TREK-1, KCNK2) is highly expressed in excitable tissues, where it plays a key role in the cellular mechanisms of neuroprotection, anaesthesia, pain perception and depression (Cohen et at., 2008). Alternative translation initiation in rat brain yields K2P2.1 potassium channels permeable to sodium (Thomas et al. 2008). The crystal structure of the human 2-pore domain K+ channel, K2P1 has been solved (Miller and Long, 2012). Multiple modalities converge on a common gate to control K2P channel function (Bagriantsev et al., 2011).  TREK-1 mediates fast and slow glutamate release in astrocytes upon GPCR activation (Woo et al. 2012). It is a mechanosensitive K+ channel, present in rat bladder myocytes, which is activated by swelling and arachidonic acid (Fukasaku et al. 2016). The M2-hinges of TREK-1 and TREK-2 channels control their macroscopic current, subcellular localization and gating (Zhuo et al. 2017). The human ortholog has acc # O95069 and has an additional N-terminal 15 aas. BL-1249, a compound from the fenamate class of nonsteroidal anti-inflammatory drugs, is known to activate K2P2.1(TREK-1), the founding member of the thermo- and mechanosensitive TREK subfamily (Pope et al. 2018).

Mammals

TREK-1 of Mus musculus (P97438)

 

 
1.A.1.9.10Potassium channel subfamily K member 16 (2P domain potassium channel Talk-1) (TWIK-related alkaline pH-activated K(+) channel 1) (TALK-1)AnimalsKCNK16 of Homo sapiens
 
1.A.1.9.11

pH-dependent, voltage-insensitive, background potassium channel protein involved in maintaining the membrane potential, KCNK9, K2P9.1 or TASK3 (TASK-3) of 374 aas  (Huang et al. 2011). Terbinafine is a selective activator of TASK3 (Wright et al. 2017). The response of the tandem pore potassium channel TASK-3 to voltage involves gating at the cytoplasmic mouth (Ashmole et al., 2009).  TASK-3 is involved in several physiological and pathological processes including sleep/wake control, cognition and epilepsy (Tian et al. 2019). N-(2-((4-nitro-2-(trifluoromethyl)phenyl)amino)ethyl)benzamide (NPBA) is an activator (Tian et al. 2019). KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels (Goutierre et al. 2019).

 

KCNK9 or TASK3 of Homo sapiens

 
1.A.1.9.12
Potassium channel subunit of 330 aas. No channel activity was observed in heterologous systems. It probably needs to associate with other proteins (i.e., KCNK3 and KCNK9) to form a functional channel (Huang et al. 2011).

KCNK15 of Homo sapiens

 
1.A.1.9.13

The Kcnk10a (TREK-2A) K+ channel of 569 aas and 6 TMSs. It localizes in the brain and seems to regulate reproduction (Loganathan et al. 2017).

TREK-2A of Danio rerio (Zebrafish) (Brachydanio rerio)

 
1.A.1.9.14

Open rectifier K+ channel 1, isoform D of 1001 aas and 6 TMSs, Ork1.

ORK1 of Drosophila melanogaster (Fruit fly)

 
1.A.1.9.2

KCNK3 K+ channel (TASK1, OAT1, TBAK1) (the K+ leak conductance). TASK1 and 3 may play a role in nontumorigenic primary hyperaldosteronism (Davies et al., 2008).  KCNK3/9/15 expression limits membrane depolarization and depolarization-induced secretion at least in part by maintaining intracellular K+ (Huang et al. 2011).

Animals

KCNK3 of Homo sapiens (AAG29340)

 
1.A.1.9.3

Neuronal 2-P (4 TMS) domain K+ membrane tension-gated channel, TRAAK (stimulated by arachidonic acid and polyunsaturated fatty acids (Fink et al., 1998). The crystal structures of conductive and nonconductive human K2P TRAAK K+ channel has been solved (Brohawn et al., 2012; Brohawn et al. 2014). Regulated by mechanical deformation of the membrane and temperature as well as polyunsaturated fatty acids (Brohawn et al., 2012). Multiple modalities converge on a common gate to control K2P channel function (Bagriantsev et al., 2011).  In the non-conductive state, a lipid acyl chain accesses the channel cavity through a 5 Å-wide lateral opening in the membrane inner leaflet and physically blocks ion passage. In the conductive state, rotation of transmembrane helix 4 about a central hinge seals the intramembrane opening, preventing lipid block of the cavity and permitting ion entry. Additional rotation of a membrane interacting TM2-TM3 segment, unique to mechanosensitive K2Ps, against TM4 may further stabilize the conductive conformation. Comparison of the structures provodes a biophysical explanation for TRAAK mechanosensitivity--an expansion in cross-sectional area up to 2.7 nm2 in the conductive state is expected to create a membrane-tension-dependent energy difference between conformations that promotes force activation (Brohawn et al. 2014).  TM helix straightening and buckling may underlie channel activation (Lolicato et al. 2014). A lipid chain blocks the conducting path in the closed state (Rasmussen 2016).

Animals

TRAAK of Mus musculus (O88454)

 
1.A.1.9.4

Outward rectifying mechanosensitive 2-P (4 TMS) domain K+ channel, TREK-2 (KCNKA; KCNK10; K2P10). Activated by membrane stretch, acidic pH, arachidonic acid and unsaturated fatty acids.  Dong et al. 2015 described crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. This provides an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac (Dong et al. 2015).  The unique gating properties of TREK-2 and the mechanisms by which extracellular and intracellular stimuli harness pore gating allosterically have been studied (Zhuo et al. 2016). TREK-2 moves from the """"down"""" to """"up"""" conformation in direct response to membrane stretch. Aryal et al. 2017 showed how state-dependent interactions with lipids affect the movement of TREK-2, and how stretch influences both the inner pore and selectivity filter. They also demonstrated why direct pore block by lipid tails does not represent theprincipal mechanism of mechanogating (Aryal et al. 2017). The M2-hinges of TREK-1 and TREK-2 channels control their macroscopic current, subcellular localization and gating (Zhuo et al. 2017). TREK-2 responds to a diverse range of stimuli. Two states, termed """"up"""" and """"down,"""" are known from x-ray structural crystallographic studies and have been suggested to differ in conductance. Brennecke and de Groot 2018 found that the down state is less conductive than the up state. The introduction of membrane stretch in the simulations shifts the state of the channel toward an up configuration. Membrane pressure changes the conformation of the transmembrane helices directly and consequently also influences the channel conductance (Brennecke and de Groot 2018). 3-d structures are known (PDB 4XDJ_!-D. Phosphatidyl-(3,5)-bisphosphate (PI(3,5)P2) activates (Kirsch et al. 2018).

Animals

TREK-2 of Rattus norvegicus
(Q9JIS4)

 
1.A.1.9.5The TWiK family muscle K+ channel protein 18 (TWiK or Two-P domain K+ channel family) (controls muscle contraction and organismal movement; Kunkel et al., 2000)AnimalsTWK-18 of Caenorhabditis elegans
(Q18120)
 
1.A.1.9.6

The pH-sensitive 2 pore (4 TMS) K+ channel, TASK-4 (Expressed in liver, lung, pancreas and other tissues; Decher et al., 2001). The response of the tandem pore potassium channel TASK-3 (TC# 1.A.1.9.11) (K(2P)9.1) to voltage involves gating at the cytoplasmic mouth (Ashmole et al., 2009). Models have revealed the convergence of amino acid regions that are known to modulate anesthetic activity onto a common three-dimensional cavity that forms a putative anesthetic binding site in tandem pore potassium channels (Bertaccini et al. 2014).

Animals

TASK-4 of Homo sapiens
(Q96T54)

 
1.A.1.9.7

Sup-9 K+ channel of 329 aas and 6 TMSs. It is involved in coordination of muscle contraction (de la Cruz et al. 2003). Activity is regulated by Sup-18 (de la Cruz et al. 2014) and by Unc-93 (TC# 2.A.1.5.8).  It may also be regulated by Sup-10 (Q17374); it may be a suppressor of Unc-93 (de la Cruz et al., 2003). Mutation of a single residue promotes gating of  this channel and of several vertebrate and invertebrate two-pore domain potassium channels (Ben Soussia et al. 2019).

Animals

Sup-9 of Caenorhabditis elegans (O17185)

 
1.A.1.9.8TWiK family of potassium channels protein 9Wormtwk-9 of Caenorhabditis elegans
 
1.A.1.9.9TWiK family of potassium channels protein 12Worm

Twk-12 of Caenorhabditis elegans