2 TMS K⁺ channel (conducts K⁺ (K_D = 8 mM); blocked by Na⁺ (190 mM) (Renart et al., 2006) and tetrabutylammonium (Iwamoto et al., 2006)). The C-terminal domain mediates pH modulation (Hirano et al., 2011; Pau et al., 2007). KcsA exhibits a global twisting motion upon gating (Shimizu et al., 2008).  Activity is influcenced 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).

Gram-positive bacteria

Skc1 (KcsA) of Streptomyces lividans

Voltage-sensitive Na⁺ channel, Na_V1.7 (Cox et al., 2006). The human orthologue, SCN3A when mutated causes cryptogenic pediatric partial epilepsy (Holland et al., 2008)

Animals

Voltage-sensitive Na⁺ channel of Rattus norvegicus

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).  Asp802 is involved in gating and action, but not binding, of pyrethroid insecticides (Du et al. 2010).

Insects

Na⁺ channel of Blattella germanica (O01307)

Ca²⁺-regulated heart Na⁺ channel, Na_v1.5 (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). Na_v1.5, the principal Na⁺ channel in the heart, possesses an ankyrin binding site; direct interaction with ankyrin-G is required for the expression of Na_v1.5 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). SCN5A mutations causing arrhythmic dilated cardiomyopathy, commonly localized to the voltage-sensing mechanism, have been identified (McNair et al., 2011).

Animals (Homo sapiens)

Na_v1.5 of Homo sapiens (2016 aas; Q14524)

The skeletal muscle Na⁺ channel, Na_V1.4 (mutations in the S4 segment cause hypokalemic periodic paralysis; Sokolov et al., 2007). Also causes myotonia; regulated by calmodulin which binds to the C-terminus of Na_v1.4 (Biswas et al., 2008). Na_V1.4 gating pores are permeable to guanidine (Sokolov et al., 2010).

Animals

Na_V1.4 of Homo sapiens (P35499)

Voltage-sensitive Na channel, type 9, α-subunit, Nav1.7 or SCN9A (orthologous to 1.A.1.10.1). Loss of function results in a channelopathy 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 ).

Animals

Nav1.7 of Homo sapiens (Q15858)

The Voltage-gated Na⁺ channel α-subunit, Na_v1.6, 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).

Animals

Na_v1.6 of Homo sapiens (Q9UQD0)

The voltage-gated Na⁺ channel α-subunit, Na_v1.9. Present in excitable membranes. Resistant to tetrodotoxin (Bosmans et al., 2011).

Animals

Na_v1.9 of Homo sapiens (Q9UI33)

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), 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 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.

Yeast

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

The Ca_v1.4 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).

Animals

Ca_v1.4 of Homo sapiens
(O60840)

T-type Ca²⁺ channel (Ca_v3.1d) in developing heart (fetal myocardium (Cribbs et al., 2001). Both Ca_v3.1 and Ca_v3.2 are permeated by divalent metal ions, such as Fe²⁺ and Mn²⁺, and possibly Cd²⁺ (Thévenod, 2010).

Animals

Ca_v3.1d of Mus musculus (Q9WUT2)

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).

Animals

NALCN of Homo sapiens (Q6P2S6)

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) 

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)

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).

Animals

TPC2 of Homo sapiens (Q8NHX9)

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)

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

Animals

Egl-19 of C. elegans (G5EG02)

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.

Animals

Tpcn1 of Mus musculus

Fission yeast Cch1/Mid1 (Yam8) Ca²⁺ channel complex (Ma et al., 2011).

Yeast

Cch1/Mid1 of Schizosaccharomyces pombe 
Cch1 (O14234)
Mid1 (Q10063) 

Ca²⁺ uptake system, Cch1/Mid1 in filamentous fungi.

Fungi

Cch1/Mid1 of Neurospora crassa 
Cch1 (Q7SCM1)
Mid1 (Q871R6) 

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 function (Radhakrishnan et al., 2011).

Animals

R-type Ca²⁺ channel of Mus musculus

The voltage-dependent L-type Ca²⁺ channel α-subunit-1C (L-type Ca_v1.2), CACNA1C (mutations cause Timothy's syndrome, a disorder associated with autism) (Splawski et al., 2006). The C-terminus of Ca_v1.2 encodes a transcription factor (Gomez-Ospina et al., 2006). Ca_v1.2 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, Ca_v1.2 (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).

Animals

CACNA1C of Homo sapiens (2221 aas; Q13936)

The voltage-dependent L-type Ca² channel α-subunit-1H (T-type Ca_v3.2), 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).

Animals

CACNA1H of Homo sapiens (2353 aas; Q95180)

Voltage-dependent L-type Ca²⁺ channel subunit α-1C (αCa_v1.2) of cardiac muscle [A C-terminal fragment of Ca_v1.2 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). Ca_v1.2 associates with the α-2, δ-1, β and γ subunits (Yang et al., 2011).

Animals

α-Ca_v1.2 of Mus muscultus (2139 aas; Q01815)

The voltage-dependent Ca²⁺ channel subunit α-1I (isoform CRA_c (2188 aas))

Animals

Ca²⁺ channel CRA_c of Homo sapiens (EAW60347) (B0QY14)

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).  Syntaxin 1A (Sx1A), SNAP-25 and synaptotagmin (Syt1), either alone or in combination, modify the kinetic properties of voltage-gated Ca(2+) channels (VGCCs) including Cav2.1 (Cohen-Kutner et al. 2010).

Animals

Cav2.1 of Rattus norvegicus (P54282)

Voltage-dependent Ca²⁺ channel -subunit 1B (2339 aas), Cav2.2 (N-type). 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).

Animals

Cav2.2 of Mus musculus (O55017)

Paramecium bursaria Chlorella virus 1 (PBCV-1) K⁺ channel, Kcv1. (The viral-encoded K⁺ channel inserts into the 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) (Reviewed by Thiel et al., 2010).

Virus

Kcv1 K⁺ channel of Chlorella virus PBCV-1

Algal virus

ATCV1 of Acanthocystis turfacea chlorella virus (A7K9J5)

Phaeovirus

Kesv of Ectocarpus siliculosus virus 1 (Q8QN67)

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; 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.

Archaea

MthK of Methanothermobacter thermoautotrophicus (O27564)

Archaea

TuoK of Thermoplasma volcanium (Q979Z2)

The Biofilm-inducing putative K⁺ channel, BikC or YugO (M. Lunderg, personal communication). BikC has an N-terminal 2 TMS + P-loop channel domain and a C-terminal NADB_Rossman superfamily domain. YugO is in a two cistronic operon where Mistic (MstX; 9.B.23; 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 (M. Lundberg, personal communication).

Bacteria

BikC of Bacillus subtilis (Q795M8)

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

Actinobacteria

Ion channel protein of Streptomyces coelicolor

Putative K⁺ channel

Cyanobacteria

K⁺ channel of Synechocystis PCC6803

PUtative K⁺ channel

Cyanobacteria

K⁺ channel of Synechocystis PCC6803

Voltage-activated, Ca² channel blocker-inhibited, Na channel, NaChBac (Ren et al., 2001; Zhao et al., 2004; Nurani 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).

Gram-positive bacteria

NaChBac of Bacillus halodurans

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)

Voltage-gated Na⁺ channel, Na_vCh. 3d-structure known (3ROW; Payandeh et al., 2011). An anionic coordination site was proposed to confer Na⁺ 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).

Bacteria

Na_vCh of Arcobacter butzleri (A8EVM5)

Bacterial voltage-gated sodium channel, Nav.  The 3-d crystal structure of the open-channel conformation is known (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 trhough the open conformation has been analyzed (Ulmschneider et al. 2013).

Bacteria

Nav of Magnetococcus sp. (strain MC-1)

6 TMS basolateral tracheal epithelial cell/voltage-gated, small conductance, K⁺ α-chain) [acts with the KCNE3 β-chain]. Mutations in human K_v7 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).

Mammals

KCNQ1 K⁺ channel of Mus musculus

    6 TMS voltage-gated K channel, KCNQ2.  Mutations cause benign familial neonatal convulsions (BNFC; epilepsy).  It forms homotetramers or heterotetramers with KCNQ3) (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).

Mammals

KCNQ2 K⁺ channel of Homo sapiens (O43526)

   6 TMS voltage-gated K⁺ channel, KCNQ3 (mutations cause benign familial neonatal convulsions (BNFC; epilepsy)) (forms homotetramers or heterotetramers with KCNQ2) (Soldovieri et al., 2006; Uehara et al., 2008)

Mammals

KCNQ3 K⁺ channel of Homo sapiens (O43525)

   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).

Mammals

KCNQ4 K⁺ channel of Homo sapiens

The KCNQ5 K channel (modulated by Zn² , pH and volume change) (Jensen et al., 2005).  A triple cysteine module within M-typ K⁺ channels mediates reciptrocal channel modulation by nitric oxide and reactive oxygen species (Ooi et al. 2013).

Animals

KCNQ5 of Mus musculus
(Q9JK45)

K⁺ voltage-gated channel, KQT-like subfamily; Kv7.1; KCNQ1 (regulated by KCNE peptides which 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) (Peroz et al., 2008; Eldstrom et al. 2010). 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 ().

Animals

KCNQ1 of Homo sapiens (P51787)

The small conductance Ca²⁺-activated K⁺ channel, SkCa2 (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).

Mammals

SkCa2 of Homo sapiens

The intermediate conductance, Ca²⁺-activated K⁺ channel, hIK1 (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 variant of the orthologous rat KCNN4 protein have been reported (Barmeyer et al. 2010).

Mammals

hIK1 of Homo sapiens (AAC23541)

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)

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). 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).

Archaea

KvAP of Aeropyrum pernix (Q9YDF8) 

Bacteria

Kv of Listeria monocytogenes (Q8Y5K1)

Alkalinizatioin-activated Ca² -selective channel, sperm-associated cation channel, CatSper, required for male fertility and the hyperactivated motility of spermatozoa. These channels require auxiliary subunits, CatSperβ, γ and %u03B4 for activity (Chung et al., 2011).  The primary channel protein is CatSper1 (Liu et al., 2007).

Mammals

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

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) 

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

Animals

Shab11 of Drosophila melanogaster

Voltage-gated K⁺ channel, chain A, Shaker-related, K_v1.2 (Crystal structure known, Long et al., 2007; Chen et al. 2010). Delemotte et al. (2010) described the effects of sensor domain mutations on molecular dynamics of Kv1.2.

Animals

K_v1.2 of Homo sapiens (P16389)

Voltage-gated K⁺ channel, Shab-related, K_v2.1 (858aas) (Crystal structure known, Long et al., 2007). Rat K_v2.1 and K_v2.2 (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 K_v2 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).

Animals

K_v2.1/K_v2.2 of Homo sapiens
(Q14721)
(Q92953)

Voltage-gated K⁺ channel, Kv1.1 (Regulated by syntaxin through dual action on channel surface expression and conductance; Feinshreiber et al., 2009).

Animals

Kv1.1 of Homo sapiens (Q09470)

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).

Animals

Kv3.3 of Homo sapiens (Q14003)

Voltage-gated delayed rectifier K⁺ channel, Kv1 of the octopus. RNA editing underlies adaption (Garrett and Rosenthal, 2012).

Animals

Kv1 of Octopus vulgaris (H2EZS9)

The voltage-gated K⁺ channel subfamily D member 3, KCND3 or K_v4.3.  Mutations cause spinocerebellar ataxia type 19 (Duarri et al. 2012).  The crystal structure with its regulatory subunit, Kchip1, has been solved (2NZ0).

Animal

KCND3 of Homo sapiens

Voltage-sensitive K⁺ channel

Animals

Shaw2 of Drosophila melanogaster

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).

Animals

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

Voltage-gated K⁺ channel subfamily D, member 2, Kv4.2 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). The C-terminus interacts with KChIP2 to influence gating, surface trafficking and gene expression (Han et al., 2006; Schwenk et al., 2008). KChIPs (229aas for KChIP4a; AAL86766) are homologous to domains in NADPH oxidases (5.B.1). Heteropoda toxin 2 (P58426; PDB, 1EMX) interactions with Kv4.3 and Kv4.1 give rise to differences in gating modifications (DeSimone et al., 2011).

Animals

Kv4.2 of Homo sapiens (Q9NZV8)

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).

Animals

Shaker of Drosophila melanogaster (CAA29917)

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

Animals

Kv9.1 of Homo sapiens
(Q96KK3)

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)

K voltage-gated ether-a-go-go-related channel, H-ERG (KCNH2; Erg; HErg; Erg1) subunit K_v11.1 (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 funtion 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).

Mammals

H-ERG of Homo sapiens (Q12809)

K⁺ voltage-gated channel, rEAG1; K_v 10.1; 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).

Animals

EAG1 of Rattus norvegicus (Q63472)

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

Bacteria

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

Plants

CASTOR of Lotus japonicus (Q5H8A6)

Plants

POLLUX of Lotus japonicus (Q5H8A5)

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

Actinobacteria

Ion channel protein of Streptomyces coelicolor

K⁺ channel protein homologue 

δ-Proteobacteria

K⁺ channels protein homologue of Stigmatella aurantiaca (Q08U57)

Putative 6 TMS potassium channel

Proteobacteria

Potassium ion channel of Myxococcus xanthus

Putative K⁺ channel

Cyanobacteria

K channel of Cyanotheca (Synechococcus) sp PCC8801

The 6TMS bacterial cyclic nucleotide-regulated, voltage independent channel, MlotiK1 (Clayton et al., 2008). Gating involves large rearrangements of the cyclic nucleotide-binding domains (Mari et al., 2011).

Bacteria

MlotiK1 of Mesorhizobium loti (Q98GN8)

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

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

Putative K⁺ channel

Proteobacteria

Putative K⁺ channel of Klebsiella varicola (D3RJS6)

Putative K⁺ channel

Proteobacteria

Putative K⁺ channel of Pseudomonas fluorescens (C3K1P0) 

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

Cyanobacteria

SynK of Synechocystis sp.

Putative voltage-dependent K+ channel

γ-Proteobacteria

K⁺ channel of Vibrio alginolytcus

Putative voltage-dependent K⁺ channel

γ-Proteobacteria

K⁺ channel of E. coli

Putative voltage-dependent K⁺ channel

Proteobacteria

K⁺ channel of Acinetobacter baumannii

Ca²⁺-activated K⁺ channel. 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).

Animals

Ca²⁺-activated K⁺ channel of Drosophila melanogaster

Large conductance Ca²  - and voltage-activated K channel, α-subunit (subunit α1), BK_Ca, Kca1.1 or MaxiK (functions with four β-subunits encoded by genes KCNMB1-4 in humans; 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), Cav2.2 (N-type; 1.A.1.11.6) where Ca²   influx through the Cav channel activates BK_Ca (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 BK_Ca 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). BK_Ca 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 serotonin receptor 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).

Animals

BK_Ca or MaxiK channel of Rattus norvegicus (Q62976)

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).

Animals

BK K⁺ channel of Caenorhabditis elegans (Q95V25)

Animals

rSlo2 of Caenorhabditis elegans (Q9Z258)

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)

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).

Plants

AKT1 of Arabidopsis thaliana

Mosses

Akt1 of Physcomitrella patens (A5PH36)

Plants

KDC1 of Daucus carota

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).

GORK of Arabidopsis thaliana (CAC17380)

Heterotetrameric K⁺ channel, KAT2/AKT2. 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)

Plants

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

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).

Plants

KAT1 of Arabidopsis thaliana (Q39128)

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).

Plants

KC1 of Arabidopsis thaliana (P92960)

Ortholog K⁺/Na⁺ pacemaker channel, Hcn4 (Scicchitano et al., 2012)

Animals

Hcn4 of Homo sapiens (Q9Y3Q4)

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) 

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).

Animals

CNGA3 of Homo sapiens (Q16281) 

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)

Hyperpolarization-activated and cyclic nucleotide-gated K⁺ channel, HCN (bCNG-1) (P_Na⁺/P_K⁺ ≈ 0.3). The human orthologue (O88703) is 863 aas in length and catalyzes mixed monovalent cation currents K⁺:Na⁺= 4:1 (Lyashchenko and Tibbs et al., 2008). Biel et al. (2009) present a detailed review of hyperpolarization-activated cation-channels. Inhibited by nicotine and epibatidine which bind to the inner pore (Griguoli et al., 2010).

Animals

HCN of Mus musculus

Heterotetrameric (3A:1B) rod photoreceptor cyclic GMP-gated cation channel, CNG (Zhong et al., 2002). 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).

Animals

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

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)

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)

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)

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

Plants

CNG3 of Arabidopsis thaliana (Q9SKD7)

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).

Plants

AtTPK4 of Arabidopsis thaliana (AAP82009)

Plants

KCO1 of Arabidopsis thaliana
(Q8LBL1)

TWIK-1 inward rectifier K⁺ channel (Enyedi and Czirják, 2010).

Mammals

TWIK-1 of Mus musculus

TREK-1 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 mechanogated, 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 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).

Mammals

TREK-1 of Mus musculus (P97438)

Neuronal 2-P (4 TMS) domain K⁺ channel, TRAAK (stimulated by arachidonic acid and polyunsaturated fatty acids (Fink et al., 1998). The crystal structure of the human K2P TRAAK K⁺ channel has been solved (Brohawn et al., 2012). 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).

Animals

TRAAK of Mus musculus (O88454)

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 (K(2P)9.1) to voltage involves gating at the cytoplasmic mouth (Ashmole et al., 2009).

Animals

TASK-4 of Homo sapiens
(Q96T54)

Sup-9 K⁺ channel (possibly regulated by unc-93; and may be a suppressor of unc-93. Another regulator of Sup-9 is Sup-10 (Q17374) (de la Cruz et al., 2003).

Animals

Sup-9 of Caenorhabditis elegans (O17185)

Twk-12 of Caenorhabditis elegans

The homo- and heteromeric glutamate receptor, GLR3.3/3.4 (Desensitized in 3 patterns: (1) by Glu alone; (2) by Ala, Cys, Glu or Gly; (3) by Ala, Cys, Glu, Gly, Ser or Asn (Stephens et al., 2008).

GLR3.3/GLR3.4 receptor of Arabidopsis thaliana
GLR3.3 (Q9C8E7)
GLR3.4 (Q8GXJ4)

GriK2; GluK2; Glur6 glutamate receptor, ionotropic kainate 2. 3-d structure known (2XXY_A). Domain organization and function have been analyzed by Das et al. (2010).  Two auxiliary subunits, Neto1 and Neto2 alter the trafficking, channel kinetics and pharmacology of the receptors.  They reduce inward rectification without altering calcium permeability (Fisher and Mott 2012).

Animals

Grik2 of Rattus norvegicus (P42260)

The NMDA receptor. The crystal structure of the N-terminal domains (GluN1 and GluN2) have been determined (PDB#3QEL; Talukder and Wollmuth, 2011). The ligand-specific deactivation time courses of GluN1/GluN2D NMDA receptors have been measured (Vance et al., 2011).

Animals

NMDA receptor of Xenopus laevis (Q91977)

Glu2 AMPA receptor (GluR-2). Interacts directly with β3 integrin (Pozo et al., 2012).  In general, integrin receptors form macromolelcular complexes with ion channels (Becchetti et al. 2010).  AMPA recpetors are regulated by S-SCAM through TARPs (Danielson et al. 2012).  The C-terminal domains of various TARPs regulate GluRs (Sager et al. 2011).  Whole-genome analyses link multiple TARP loci to childhood epilepsy, schizophrenia and bipolar disorder (Kato et al. 2010). Thus, TARPs emerge as vital components of excitatory synapses that participate both in signal transduction and in neuropsychiatric disorders.

Animals

GluR-2 of Homo sapiens (P42262)

GIC, NMDA-subtype, Grin C2 (highly permeable to Ca²⁺-monovalent cations). A single residue in the GluN2 subunit controls NMDA receptor channel properties via intersubunit interactions (Retchless et al., 2012). Memantine (Namenda) is prescribed as a treatment for moderate to severe Alzheimer's Disease. Memantine functions by blocking the NMDA receptor, and the sites of interaction have been identified (Limapichat et al. 2013).

Animals

NMDA receptor, Grin C2, of Homo sapiens

AMPA glutamate receptor 3 (GluR3) (non-selective monovalent cation channel and Ca²⁺  channel) (Ayalon et al., 2005; Midgett et al., 2012). Regulated by AMPA receptor regulatory proteins (TARPs) including stargazin and CNIH auxiliary subunits (Kim et al., 2010; Straub and Tomita, 2011; Jackson and Nicoll, 2011; Bats et al., 2012). The domain architecture of a calcium-permeable AMPA receptor in a ligand-free conformation has been solved (Midgett et al., 2012). The TARP, stargazin, is elevated in the somatosensory cortex of Genetic Absence Epilepsy Rats (Kennard et al. 2011).

Animals

GluR3 of Homo sapiens (P42263)

The heteromeric cation (Ca²⁺) channel/glutamate (NMDA) receptor NMDAR1/NMDAR2A/NMDAR2B/NMDAR2C) (Monyer et al., 1992). Note: NR2B is the same as NR3 or subunit epsilon (Schüler et al., 2008). Mediates voltage- and Mg²⁺- dependent control of Na⁺ and Ca²⁺ permeability (Yang et al., 2010).

Animals

NR1/NR2A or NR2B or NR2C of Rattus norvegicus
NR1 (Q05586)
NR2A (O08948)
NR2B (Q00960)
NR2C (Q62644)

Glutamate ionotropic K⁺ channel receptor, GluR0 (5TMSs). X-ray structure available (PDB: 1IIT)

Bacteria

GluR0 of Synechocystis sp. PCC6803

Probable Ionotropic glutamate receptor (GluR)

Bacteriodetes

GluR homologue of Algoriphagus sp. PR1 (A3I049)

Probably Ionotropic glutamate receptor (GluR) 

Chlorobi

GluR homologue of Chlorobium luteolum (Q3B5G3)

Probable Ionotropic glutamate receptor (GluR)

Proteobacteria

GluR homologue of Vibrio fischeri (B5FDH7)

High-affinity electrogenic ammonia/methylammonia transporter (allosterically activated by the C-terminus (Loqué et al., 2009).  NH_4⁺ is stable in the AmtB pore, reaching a binding site from which it can spontaneously transfer a proton to a pore-lining histidine residue (His168). The substrate diffuses down the pore in the form of NH₃, while the proton is cotransported through a highly conserved hydrogen-bonded His168-His318 pair (Wang et al. 2012).

Plants

Amt1 of Arabidopsis thaliana (P54144)

Ammonia-specific uptake carrier, Amt2. For AMT2 from Arabidopsis thaliana NH₄⁺ is the recruited substrate, but the uncharged form NH₃ is conducted.  AtAMT2 partially co-localizes with electrogenic AMTs and conducts methylamine with low affinity (Neuhäuser et al., 2009). This may explain the different capacities of AMTs to accumulate ammonium in the plant cell.

Plants

Amt2 of Arabidopsis thaliana

Ammonium/methyl ammonium uptake permease, AmtB (may need AmtB to concentrate [¹⁴C]methyl ammonium (Paz-Yepes et al., 2007))

Cyanobacteria

AmtB of Synechococcus sp CC9311 (Q0IDE4)

Plants

Amt1;4 of Arabidopsis thaliana (Q9SVT8)

Amt2 NH₄⁺/CH₃-NH₃⁺ transporter, subject to allosteric activation by a C-terminal region (Loqué et al., 2009).

Archaea

Amt2 of Archaeoglobus fulgidus (O28528)

Amt1;1, a proposed NH₄⁺:H⁺ sumporter (Ortiz-Ramirez et al., 2011)

Plants

Amt1;1 of Phaseolus vulgaris (E2CWJ2)

Ammonium transporter 2, AmtB

AmtB of Dictyostelium discoideum

Yeast

Mep2 of Candida albicans (Q59UP8)

Rhesus (Rh) type C glycoprotein NH₃/NH₄⁺ transporter, RhCG (also called tumor-related protein DRC2) (Bakouh et al., 2004; Worrell et al., 2007). Zidi-Yahiaoui et al. (2009) have described characteristics of the pore/vestibule. The structure is known to 2.1 Å resolution (Gruswitz et al., 2010). Each monomer contains 12 transmembrane helices, one more than in the bacterial homologs. Reconstituted into proteoliposomes, RhCG conducts NH₃ to raise the internal pH. Models of the erythrocyte Rh complex based on the RhCG structure suggest that the erythrocytic Rh complex is composed of stochastically assembled heterotrimers of RhAG, RhD, and RhCE (Gruswitz et al., 2010).

Animals

RhCG of Homo sapiens (Q9UBD6)

Rhesus (Rh) type B glycoprotein NH₃/NH₄⁺ transporter, RhBG (~50% identical to type C) (Lopez et al., 2005; Worrell et al., 2008). Electrogenic NH₄⁺ transport is stimulated by alkaline pH_(out) but inhibited by acidic pH_(out) (Nakhoul et al., 2010).

Animals

RhBG of Homo sapiens (Q9H310)

Rhesus (Rh) complex (tetramer: RhAG₂, RhCE₁, RhD₁) (Exports ammonia from human red blood cells) (Conroy et al., 2005)

Animals

The RhAG/RhCE/RhD, complex of Homo sapiens
RhAG (Q02094)
RhCE (P18577)
RhD (Q02161)

The RH50 NH₃ channel (most like human Rh proteins TC# 1.A.11.4.1 and 2; 36-38% identity) (Cherif-Zahar et al., 2007). The Rh CO₂ channel protein (3-D structure ± CO₂ available) (3B9Z_A; 3B9Y_A) (Li et al., 2007; Lupo et al., 2007) (also transports methyl ammonia) (Weidinger et al., 2007).

Gram-negative bacteria

RH50 of Nitrosomonas europaea (Q82X47)

Kidney rhesus glycoprotein p2 (Rhp 2). Transports NH₃ and methylammonium (Nakada et al., 2010).

Animals

Rhp2 of Triakis scyllium (D0VX38)

Rhesus-like glycoprotein A (Rh50-like protein RhgA)

RhgA of Dictyostelium discoideum

Animals

CLIC-5A of Homo sapiens (Q53G01)

The Janus protein, CLIC2. The 3-D structure of its water soluble form has been determined at 1.8 Å resolution (Cromer et al., 2007). CLIC2 interacts with the skeletal ryanodine receptor (RyR1) and modulates its channel activity (Meng et al., 2009).

Animals

CLIC2 of Homo sapiens (O15247)

Intracellular Cl^- channel-3 (CLIC3). The 3-d structure is known (3FY7). This protein is associated with pregnancy disorders (Murthi et al., 2012). 

Animals

CLIC3 of Homo sapiens (O95833)

The Ca-activated chloride channel-6 (Lee et al., 2011).

Animals

Ca-CLC-6 of Xenopus laevis (F7IYU6)

Hypothetical protein, HP

Plants

HP of Oryza sativa (B8AFH9)

Sll0103

Bacteria

Sll0103 of Synechocystis (Q55874)

The YfbK/CaClC homologue

Bacteria

YfbK of E. coli (P76481)

Von Willebrand factor type A protein, vWFA. (905 aas; 2 N-terminal and 1 C-terminal TMSs)

Bacteria

vWFA of Chloroflexus aurantiacus (A9WIT9)

Bacterial homologue, BatB, of mammalian Ca-CLC channels (N- and C-terminal TMSs)

Bacteria

BatB of Myxococcus fulvus (F8CM01)

The TEGT protein. Also called Bax Inhibitor-1. It forms a Ca²⁺-permeable channel (Bultynck et al., 2011).

Animals

TEGT of Homo sapiens (P55061)

The YccA protein, an inhibitor of FtsH. May share a similar mechanism of action as BI-1 in regulation apoptsis upon prolonged secretion stress (van Stelten et al., 2009).

Bacteria

YccA of E. coli (P0AAC6)

The YbhL (AceP) protein. Possibly a pmf-dependent acetate uptake transporter. [¹⁴C]Acetate uptake was inhibited by CCCP as well as cold acetate, serine, α-ketoglutarate, lactate, and succinate (M. Inouye, personal communication).

Bacteria

YbhL of E. coli (P0AAC4)

YetJ

Bacteria

YetJ of Bacillus subtilis (O31539)

The NMDA receptor glutamate binding chain. Also called Protein lifeguard-1, putative MAPK-activating protein PMO2, and transmembrane BAX inhibitor motif-containing protein 3 (TMBIM3, GRINA, LFG1, NMDARA1). The human orthologue is Q7Z429.

Animals

NMDA receptor glutamate binding chain of Homo sapiens (Q63863)

Glutamate Receptor Gr2

Ichthosporea

Gr2 of Capsaspora owczarzaki (E9CCY6)

Golgi anti-apoptotic protein, GAAP.

Viruses

GAAP of Vaccinia virus (A2VCJ6)

Ionotropic glutamate receptor; N-methyl-D-aspartate-associated protein 1 (glutamate-binding).

Animals

Gr1 of Salmo salar (B5X2N0)

The BH3-only protein, Ynl205c (Büttner et al., 2011)

Yeast

Ynl305c of Saccharomyces cerevisiae (P48558)

7 TMS integral membrane protein

Bacteria

Uncharacterized membrane protein of Rhodopirellula baltica

Viral protein HWLF3 (342 aas; 7 TMSs)

Viruses

HWLF3 of human cytomegalovirus, HHV-5 (Q03307)

Formate uptake/efflux permease.  Catalyzes bidirectional transport, has a pentameric aquaporin-like (TC# 1.A.8) structure, and may function by a channel-type mechanism (Falke et al., 2009; Wang et al. 2009). The structure at 2.25 Å resolution has been determined (Wang et al., 2009).  Encoded in an operon with pyruvate-formate lyase, PflB.  A pyruvate:formate antiport mechanism has been suggested (Moraes and Reithmeier 2012).

Bacteria

FocA of E. coli (P0AC23)

Probable formate transporter 2 (Formate channel 2), FocB

Bacteria

FocB of Escherichia coli

Formate channel, FocA. Competition of formate by Thr90 from the Ω loop may open the channel (Waight et al., 2010).

Bacteria

FocA of Vibrio cholerae (F9A868)

Probable formate uptake permease (Kuzminov and Stahl, 1997).

Bacteria

FdhC of Methanobacterium thermoformicium

Nitrate uptake porter, NitB (Unkles et al., 1991; 2011)

Fungi

NitB of Emericella (Aspergillus) nidulans (Q5AST3)

Probable formate uptake permease (Wood et al., 2003).

Archaea

FdhC of Methanococcus maripaludis

Uncharacterized transporter YwcJ

YwcJ of Bacillus subtilis

Hydrosulfide (hydrogen sulfide; HS^-), Fnt3 (Hsc) channel.  Also probably transports chloride, formate and nitrite. The 3-d crystal structure (2.2Å resolution in the closed state) is known (PDB# 3TE2) (Czyzewski and Wang, 2012). The Fnt3 gene is linked to the asrABC operon encoding the sulfite (SO₃^2-) reductase that gives HS^- as the product (Czyzewski and Wang 2012).

Bacteria

Hsc or Fnt3 HS^- channel of Clostridium difficile (Q186B7)

Inner membrane protein, YfdC (310aas; 6 TMSs)

Bacteria

YfdC of E. coli (P37327)

The plasma membrane Ca² -activated chloride channel, TMEM16A (Anoctamin 1a) (Huang et al., 2012; Chen et al. 2011). The mouse orthologue (Q8BHY3), TMEM16A (956aas), is localized to the apical membranes of epithelia as well as intracellular membranes in many cell types. Knockout mice show diminished rhythmic contraction of gastric smooth muscle (Huang et al., 2009). ANO1 is also required for normal tracheal development (Ousingsawat et al., 2009). Expression is upregulated by epidermal growth factor (Mroz and Keely, 2012). Novel 5-substituted benzyloxy-2-arylbenzofuran-3-carboxylic acids are inhibitors (Kumar et al., 2012). TMEM16A channels contribute to the myogenic response in cerebral arteries (Bulley et al., 2012). Membrane stretch activates arterial myocyte TMEM16A channels, leading to membrane depolarization and vasoconstriction. A local Ca²   signal generated by nonselective cation channels stimulates TMEM16A channels to induce myogenic constriction (Bulley et al., 2012).  Ca² /calmodulin activates bicarbonate (anion) transport (Jung et al. 2012).  Exists in the membrane as a homodimer where the cytoplasmic N-terminus functions in dimerization (Tien et al. 2013).  TMSs 5-6 may comprise parts of the pore-loop that controls Cl^- conductance (Adomaviciene et al. 2013).

Animals

Anoctamin 1a of Homo sapiens (Q5XXA6)

Anoctamin 1, isoform b (Gnathodiaphyseal dysplasia 1 protein homologue) (39% identical to Anoctamin 1a) (Planells-Cases and Jentsch, 2009).

Anoctamin 1b of Homo sapiens (Q75UR0)

TMEM16B (Anoctamin-2, ANO2) anion channel.  Exists in the membrane as a homodimer where the cytoplasmic N-terminus functions in dimerization (Tien et al. 2013).  TMSs 5-6 may comprise parts of the pore-loop that controls Cl^- conductance (Adomaviciene et al. 2013).

Animals

TMEM16B of Homo sapiens (Q9NQ90)

Anoctamin-6 (TMEM16F) Ca²⁺-dependent phospholipid scramblase (flippase) (Suzuki et al., 2010). Defects cause Scott syndrome. It is an essential component of the outwardly rectifying chloride channel (Martins et al., 2011; Keramidas and Lynch 2012).  It has also been reported to be an anion channel with delayed Ca²⁺ activation (Adomaviciene et al. 2013) as well as a Ca²⁺-activated cation channel with activity that is required for lipid scrambing (Yang et al. 2012).  However, Suzuki et al. (2013) showed that TMEM16F is a Ca²⁺-dependent phospholipid scramblase that exposes phosphatidylserine (PS) to the cell surface but lacks calcium-dependent chloride channel activity.  TMEM16C, 16D, 16G and 16J also had Ca²⁺-dependent scramblase but not channel activity (Suzuki et al. 2013).

Animals

Anoctamin-6 of Homo sapiens (Q4KMQ2)

Uncharacterized protein

Fungi

Uncharacterized protein of Batrachochytrium dendrobatidis

Anoctamin-like protein

Amoebozoa (Slime molds)

amoctamin-like protein of Dictyostelium purpureum

Uncharacterized protein

Stremenopiles

unchacterized protein of Aureococcus anophagefferens

Ca-ClC Family homologue

Ciliates

Ca-ClC homologue of Paramecium tetraurelia (A0CAP8)

Ciliate CaClC homologue

Alveolata

CaClC homologue of Paramecium tetraurelia (A0CIB0)

TMC2, like TMC1, plays a role in hearing and gravity detection (Kawashima et al., 2011).  Required for normal function of cochlear hair cells, possibly as a Ca²⁺ channel (Kim and Fettiplace 2013).

Animals

TMC2 of Mus musculus (Q8R4P4)

Transmembrane channel-like protein-B, Tmc8

Animals

Tmc8 of Mus musculus (Q7TN58)

Hypothetical protein, HP

Choanoflagellida

HP of Salpingoeca sp. (F2U2C0)

Hypothetical protein, HP

Ichthyosporea

HP of Capsaspora owczarzaki (E9C7I1)

Transmembrane channel-like protein 7, TMC7

Animals

TMC7 of Acromyrmex echinatior (F4X8H9)

Transmembrane channel-like protein-1, Tmc1. Also called Transmembrane cothlear-expressed protein-1, Beethoven protein and deafness protein.  Required for normal function of cochlear hair cells, possibly as a Ca²⁺ channel (Kim and Fettiplace 2013).

Animals

Tmc1 of Mus musculus

The sodium sonsor/cation conductance channel activated by high extracellular Na⁺, Tmc-1 (Chatzigeorgiou et al. 2013).  It functions in salt taste chemosensation and salt avoidance and is an ionotropic sensory receptor.

Animals

Tmc-1 of Caenorhabditis elegans

DUF590 family protein

Slime molds

DUF590 protein of Dicyostelium discoideum (Q54BH1)

Water mold Anoctamin-like protein

Animal

Anoctamin-like protein of Phytophthora infestans (D0NGF4)

Uncharacterized protein

Fungi

Uncharacterized protein of Schizosaccharomyces japonicus

Anoxtamin-like protein

Alveolata

Anoctamin-like protein of Oxytricha trifallax

Tic110 channel protein. The x-ray structure (4.2Ĺ resolution) of Tic110B and C from Cyanidioschyzon merolae is known (Tsai et al., 2013). The C-terminal half of Tic110 posesses a rod-shaped helix-repeat structure that is too flattened and elongated to be a channel. The structure is most similar to the HEAT-repeat motif that functions as scaffolds for protein-protein interactions (Tsai et al., 2013).

Rhodophyta

Tic110 of Cyanidioschyzon merolae (M1V6H9)

Matrix protein, M2, an acid activated drug-sensitive proton channel.  Transport involves binding to the four His-37s and transfer to water molecules on the inside of the channel (Acharya et al., 2010).  Functional properties and structure are known (Hong and Degrado 2012). 

Viruses

M2 of influenza virus type A

ATP-activated inward rectifier K channel, IRK1 (also called ROMK or KIR1.1) (regulated by Sur1, allowing ATP sensitivity; also activated by phosphatidylinositol 4,5-bisphosphate (PIP) with affinity to PIP controlled by protein kinase A phosphorylation (which increases affinity for PIP)) and protein kinase C phosphorylation (which decreases affinity for PIP (Zeng et al., 2003). Alternariol (AOH), the most important mycotoxin produced by Alternaria species, which are the most common mycoflora infecting small grain cereals worldwide, causes loss of cell viability by inducing apoptosis. AOH-induced apoptosis through a mitochondria-dependent pathway is characterized by p53 activation, an opening of the mitochondrial permeability transition pore (PTP), loss of mitochondrial transmembrane potential (ΔΨm), a downstream generation of O₂^- and caspase 9 and 3 activation (Bensassi et al., 2012). 

Animals

IRK1 of Homo sapiens (P48048)

G-protein-activated inward rectifying K  channel, Kir3.2 or GIRK (Inanobe et al., 2011; Yokogawa et al. 2011).  Important in regulating heart rate and neuronal excitability.  Activated by binding of the Gbetagamma subunit complex to the cytoplasmic pore gate (Yokogawa et al. 2011).

Animals

Kir3.2 of Homo sapiens (P48051)

Inward rectifying potassium channel 16, Kir5.1. (Potassium channel subfamily J member 16), KCNJ16.  Involved in pH and fluid regulation.  Forms heteromers with Kir4.1/KCNJ10 or Kir2.1/KCNJ2.

G protein-activated inward rectifying K⁺ channel 1 (Kir3.1; IRK3; GIRK1). Regulates the heartbeat in humans. Phosphatidylinositol bisphosphate (PIP2) activates by opening the intracelluar G-loop gate (Meng et al., 2012).

Animals

Kir3.1 (IRK3) of Homo sapiens (P48549)

ATP-sensitive inward rectifying K  channel 8, Kir6.1. Acts with Sur2B (3.A.1.208.23). Channel activity is inhibited in oxidative stress via S-glutathionylation (Yang et al., 2011). Oxidative sensitivity is dependent on Cys176 (Yang et al., 2011).

Animals

Kir6.1 of Homo sapiens (Q15842)

G-protein enhanced inward rectifier K channel 2, IRK2 (Kir2.1)(Andersen-Tawil Syndrome (ATS-1) protein; the V302M mutation causing the syndrome, alters the G-loop cytoplasmic K conduction pathway) (Bendahhou et al., 2003; Ma et al., 2007). (Blocked by chloroquine which binds in the cytoplasmic pore domain (Rodriguez-Menchaca et al., 2008)). Forms heteromultimers with Kir3.1 and Kir3.4 (Ishihara et al., 2009). A C-terminal domain is critical for the sensitivity of Kir2.1 to cholesterol (Epshtein et al., 2009). Flecainide increases Kir2.1 currents by interacting with cysteine 311, decreasing the polyamine-induced rectification (Caballero et al., 2010).

Animals

IRK2 of Homo sapiens (P63252)

Cranial nerve inward rectifying K⁺ channel, Kir2.4 (IRK4) (Töpert et al., 1998)

Animals

Kir2.4 of Rattus norvegicus (O70596)

Kidney/pancreas/muscle ATP-senstive, ER/golgi K⁺ channel, ROMK (Kir6.2) (Boim et al., 1995) (three alternatively spliced isoforms are called ROMK1-3). Involved in congenital hyperinsulinism (Lin et al., 2008). Regulated by Ankyrin-B (Li et al., 2010). ATP activates ATP-sensitive potassium channels composed of mutant sulfonylurea receptor 1 and Kir6.2 with diminished PIP2 sensitivity (Pratt and Shyng, 2011). This channel protects the myocardium from hypertrophy induced by pressure-overloading (Alvin et al., 2011). Domain organization studies show which domains in Sur and Kir6.2 interact (Wang et al. 2012).  KATP channels consisting of Kir6.2 and SUR1 couple cell metabolism to membrane excitability and regulate insulin secretion in pancreatic beta cells, and mutations in the former protein can compensate for mutations in the latter (Zhou et al. 2013).  Mutations cause inactivation of channel function by disrupting PIP2-dependent gating (Bushman et al. 2013).

Animals

ROMK of Rattus norvegicus (P70673)

The inward-rectifier k+ channel, Kir2.2 at the 3-d structure at 3.1 Å resolution is available (Tao et al., 2009). (70%v identical to Kir2.1 (TC # 1.A.2.1.2)). The structural basis of PIP2 activation of Kir2.2 has been presented (Hansen et al., 2011).

Animals

Kir2.2 of Homo sapiens (Q14500)

Bacteria

KirBac1.1 OF Burkholderia Pseudomallei (IP7BA; gi33357898)

The KirBac3.1 K⁺ channel (a dimer of dimers with gating visualized by atomic force microscopy, Jaroslawski et al., 2007) (regulated by binding lipids, G-proteins, nucleotides, and ions (H⁺, Ca²⁺, and Mg²⁺)). 3-D structure available (1XL6_A).

Bacteria

KirBac3.1 of Magnetospirillum magnetotacticum  (D9N164)

ATP-sensitive inward rectifying Kir K channel (Choi et al. 2010).

Bacteria

Kir K⁺ channel of Chromobacterium violaceum

Putative K⁺ channel

Cyanobacteria

K⁺ channel of Synechocystis PCC 6803

BCL2/Adenovirus E1B interacting protein, NIP3

Animals

NIP3 of Caenorhabditis elegans (Q09969)

The mitochondrial apoptosis-inducing channel-forming protein, BAX.  The C-terminal helix mediates membrane binding and pore formation (Garg et al. 2012). BAX pores are large enough to allow cytochrome c release and it activates the mitochondrial permeabilty transition pore; both play a role in programmed cell death, but the latter is quantitatively more important (Gómez-Crisóstomo et al. 2013). Bax functions like a holin when expressed in bacteria (Pang et al. 2011).

Metazoa

BAX of Homo sapiens (Q07812)

The mitochondrial apoptosis-inducing channel-forming protein, BAK. 3-D structures are known (2IMT_A).  Functions like a holin when expressed in bacteria (Pang et al. 2011).

Metazoa

BAK of Homo sapiens (Q16611). 

The BH3-only (Mcl-1) protein (mediates apoptosis). (3-d strucure known)

Animals

BH3-only of Homo sapiens (B4DG83)

Pro-survival Bcl-w protein.  Binds the BH3-only protein Bop to inhibit Bop-induced apoptosis (Zhang et al. 2012).  The structure is known (PDB# 1MK3).

Animals

Bcl-w of Homo sapiens

Large mechanosensitive ion channel: MscL; catalyzes efflux of ions (slightly cation selective), osmolytes and small proteins. Protein-lipid interactions are important for gating, dependent on TMS tilting (Iscla et al., 2011b).

Bacteria

MscL of E. coli (P0A742)

MscL (activated by arachidonate (Balleza et al., 2010), 45% identical to MscL of Bacillus subtilis (1.A.22.1.3)).

MscL of Rhizobium etli (Q2KCQ1)

The pentameric MscL channel (Iscla et al., 2011).

Bacteria

MscL of Staphylococcus aureus (P68805)

MscL; rescues cells form osmotic downshift (Bucarey et al., 2012).

Bacteria

MscL of Micromonospora aurantica  (D9T6D3)

Large-conductance mechanosensitive channel, MscL

MscL of Synechococcus sp.

Large-conductance mechanosensitive channel, MscL

Bacteria

MscL of Leuconostoc citreum

Large-conductance mechanosensitive channel, MscL

Bacteria

MscL of Renibacterium salmoninarum

Putative mechanosensative channel, YjeP (1107aas; 13TMSs in a 1 + 12 arrangement).  Encoded in an operon with phosphatidyl serine decarboxylase (Moraes and Reithmeier 2012).

Bacteria

YjeP of E. coli (P39285)

Major MscS channel protein, YggB. Seven residues, mostly hydrophobic, in the first and second transmembrane helices are lipid-sensing residues (Malcolm et al., 2011).  X-ray structures are available (Lai et al. 2013).

Bacteria, archaea, yeast, plants

YggB of E. coli (P0C0S1)

MscS protein.  The x-ray structure at 4.2 Å is available (Lai et al. 2013).

Proteobacteria

MscS of Helicobacter pylori

Putative mechanosensitive channel, YbiO (741 aas; 10TMSs)

Bacteria

YbiO of E. coli (P75783)

Mechanosensitive channel, small conductance, YggB (533 aas; 6-7TMSs).  Mediates glutamate efflux (Becker et al. 2013).

Bacteria

YggB of Corynebacterium glutamicum (P42531)

Uncharacterized MscS homologue

Proteobacteria

MscS homologue of Helicobacter pylori

Putative mechanosensative channel, YnaI (344aas; 4TMSs)

Bacteria

YnaI of E. coli (P0AEB5)

Plant plastid mechanosensitive channel MscS-like-2 (Msl2) (controls plastid organellar morphology, as does Msl3) (Haswell and Meyerowitz, 2006; Haswell et al., 2008; Jensen and Haswell, 2012). 

Plant

Msl2 of Arabidopsis thaliana (Q56X46)

MscM (YbdG) is a distant member of the MscS family. It displays miniconductance (MscM) activity (Schumann et al., 2010).

Bacteria

MscM (YbdG) of E. coli (P0AAT4)

Mechanosensitive channel, MscS

Archaea

MscS of Sulfolobus islandicus (C4KE93)

Putative small conductance mechanosensitive channel; Calcium channel, MacS

Fungi

MacS of Mycosphaerella graminicola (Zymoseptoria tritici)

The cyclic nucleotide-binding MscS homologue, MT2508 (the C-terminal domain is the CAP_ED domain CD00038). It lacks mechanosensitivity but is ligand-gated by cyclic nucleotides (Caldwell et al., 2010).

Bacteria

MscS homologue, MT2508 of Mycobacterium tuberculosis (P71915)

Algae

Msc1 of Chlamydomonas reinhardtii (A3KE12)

MscS homologue

Actinobacteria

MscS homologue of Streptomyces coelicolor

MscS homologue

Proteobacteria

MscS of Myxococcus xanthus

Connexin 43 (gap junction α-1 protein), CX43 (transports ATP, ADP and AMP better than CX32 does; Goldberg et al., 2002). Hemichannels mediate efflux of glutathione, glutamate and other amino acids as well as ATP (Stridh et al., 2008; Kang et al., 2008). CX43 has a half life of ~3 h due to ubiquitination and lysosomal and proteasomal degradation (Leithe and Rivedal, 2007). Cx43 and Cx46 regulate each other's expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells (Banerjee et al., 2011). A mutant form of Connexin 43 causes Oculodentodigital dysplasia (Gabriel et al., 2011).

Animals

CX43 of Rattus norvegicus

Heteromeric connexin (Cx)32/Cx26) (transports cAMP, cGMP and all inositol phosphates with 1-4 esterified phosphate groups (homomeric Cx26(β2) or homomeric Cx32 do not transport the inositol phosphates as well) (Ayad et al., 2006). The GJB2 gene encodes connexin 26, the protein involved in cell-cell attachment in many tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss as well as various skin disease phenotypes (Iossa et al., 2011). TMS1 regulates oligomerization and function Jara et al., 2012().

Animals

Cx26/Cx32 of Homo sapiens
Cx26 (P29033)
Cx32 (P08034)

Heteromeric (or homomeric) Connexin46/Connexin50 junction (Cx46/Cx50)  Mutations in CX46 or Cx50 cause cataracts) (Derosa et al., 2007; Wang and Zhu 2012). Cx43 and Cx46 regulate each other's expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells (Banerjee et al., 2011).  The N-terminal half of connexin 46 appears to contain the core elements of the pore and voltage gates (Kronengold et al. 2012).

Animals

Cx46/Cx50 of Homo sapiens:
Cx46 (Q9Y6H8)
Cx50 (P48165)

Animals

Connexin37 of Homo sapiens (P35212)

Connexin 3 complex (Cx30.2; Cx31.3). ATP is released from cells that stably expressed CX30.2 in a medium with low calcium, suggesting a hemichannel-based function. Liang et al. (2011) suggested that it shares functional properties with pannexin hemichannels rather than gap junction channels.  Defects cause hearing loss due to partial loss of channel activity (Su et al. 2012).

Animals

Cx30.2 of Homo sapiens (Q8NFK1)

Invertebrate cordate Connexin 47 (White et al., 2004).

Tunicates

Connexin 47 of Halocynthia pyriformis (Q6U1M0)

Inverebrate cordate Connexin (Hervé et al., 2005).

Tunicates

Connexin of Oikopleura dioica (E4YIP4)

Leech innexin, Inx2 (Kandarian et al. 2012; Firme et al. 2012)

Animals

Inx2 of Hirudo verbana

Innexin-14 (Protein Opu-14)

Inx-14 of Caenorhabditis elegans

Innexin-6 (Protein Opu-6)

Inx-6 of Caenorhabditis elegans

Innexin Inx4 (Innexin-4) (Protein zero population growth)

Zpg of Drosophila melanogaster

Leech innexin, Inx6 (Kandarian et al. 2012; Firme et al. 2012)

Animals

Inx6 of Hirudo verbana

Pannexin-1 (reported to form functional, single membrane, cell surface channels (Penuela et al., 2007)). Pannexin1 is part of the pore forming unit of the P2X(7) receptor death complex (Locovei et al., 2007). It can catalyze ATP release from cells (Huang and Roper, 2010) and promote ATP signalling in mice (Suadicani et al. 2012). Pannexin1 and pannexin2 channels show quaternary similarities to connexons but different oligomerization numbers (Ambrosi et al., 2010). Pannexin 1 constitutes the large conductance cation channel of cardiac myocytes (Kienitz et al., 2011). Pannexin 1 (Px1, Panx1) and pannexin 2 (Px2, Panx2) underlie channel function in neurons and contribute to ischemic brain damage (Bargiotas et al., 2011). Single cysteines in the extracellular and transmembrane regions modulate pannexin 1 channel function (Bunse et al., 2011).  Spreading depression triggers migraine headaches by activating neuronal pannexin1 (panx1) channels  (Karatas et al. 2013).

Vertebrates

Pannexin-1 of Homo sapiens (gi39995064)

Pannexin1 and pannexin2 channels show quaternary similarities to connexons but different oligomerization numbers (Ambrosi et al., 2010). Pannexin 1 (Px1, Panx1) and pannexin 2 (Px2, Panx2) underlie channel function in neurons and contribute to ischemic brain damage (Bargiotas et al., 2011).

Vertebrates

Pannexin-2 of Homo sapiens (Q96RD6)

Pannexin-3 is reported to form functional, single membrane, cell surface channels (Penuela et al., 2007)). It functions as an ER Ca²⁺ channel, hemichannel, and gap junction to promote osteoblast differentiation (Ishikawa et al., 2011).

Vertebrates

Pannexin-3 of Homo sapiens (gi16418453)

Leucine-rich repeat-containing protein 8A with N-terminal pannexin-like domain, LRRC8A. The first two TMSs of the 4 TMS protein appear as DUF3733 in CDD (Abascal and Zardoya, 2012). The C-terminal soluble domain shows sequence similarity to the heme-binding protein Shv (9.A.63.1.1) and pollen-specific leucine-rich repeat extension-like proteins (3.A.20.1.1).

Animals

LRRC8A of Homo sapiens (Q8IWT6)

Mg²⁺, Co²⁺ transporter, MgtE

Gram-positive bacteria

MgtE of Bacillus firmus (Q45121)

The Mg²⁺ transporter, MgtE. The crystal structure of the N-terminal hydrophilic domain has been determined to 2.3Å resolution (Hattori et al., 2007) (>50% identical to 9.A.19.1.1).

Bacteria

MgtE of Thermus thermophilus (Q5SMG8)

Mg²⁺, Co²⁺ transporter, MgtE

Gram-negative bacteria

MgtE of Providencia stuartii (Q52398)

MgtE homologue (function unknown)

Archaea

MgtE homologue of Methanobacterium thermoautotrophicum (O26717)

Mg² transporter, SLC41A1 (10-11 TMSs) (Wabakken et al., 2003; Schmitz et al., 2007; Kolisek et al., 2008). Regulated by Mg² -dependent endosomal recycling through its N-terminal cytoplasmic domain (Mandt et al., 2011).  Mutations result in a nephronophthisis (NPHP)-like ciliopathic phenotype (Hurd et al. 2013).

Animals

SLC41A1 of Homo sapiens

Probable Mg²⁺ transporter, SLC41A2 (10-11 TMSs) (63% identical to SLC41A1) (Wabakken et al., 2003; Schmitz et al., 2007)

Formerly-designated solute carrier protein (SLC) 41A3

FXYD6 regulator of Na,K-ATPase in the ear and taste buds (95 aas; Delprat et al., 2007; Shindo et al., 2011)

Animals

FXYD6 of Homo sapiens (Q9H0Q3)

Frog urinary bladder ADH-regulated urea transporter

Animals

Urea transporter of Rana esculenta (O57609) 

THe Urea transporter channel protein (3-d structure (2.3 Å resolution) available) (Levin et al., 2009).

Bacteria

Urea channel of Desulfovibrio vulgaris (A1VEP3)

Bacteria

Utp of Actinobacillus pleuropneumoniae

Putative amide transporter (AmiS) (Wilson et al., 1995).

Bacteria

AmiS of Pseudomonas aeruginosa

Proton-gated urea transport channel (UreI) (pH-sensitive). Allows the transmembrane flow of urea, hydroxyurea and (at a low rate) water. K_B for urea is ~150mM (Sachs et al., 2006; Scott et al., 2010). Transport kinetics and selectivity have been defined (Gray et al., 2011).  The 3-d structure reveals a hexameric protein with a channel included within the twisted 6 TMS bundle of each protomer.  It displays a two helix hairpin structure repeated three times around the central axis of the channel (Strugatsky et al. 2012). 

Bacteria

UreI of Helicobacter pylori

The hexameric ring urea/acetamide/small amide channel, UreI (7 TMSs) (Huysmans et al., 2012).

Bacteria

UreI of Bacillus cereus (Q814I5)

Ryanodine receptor Ca²⁺ release channel, RyR2 (causes Ca²⁺ release from the E.R. and causes cardiac arrhythmia) (Chelu and Wehrens, 2007). (Associates with FKBP12.6, but phosphorylation by protein kinase A on serine-2030 causes dissociation (Jones et al., 2008)).

Animals

Cardiac muscle RyR-CaC of Homo sapiens

The Ryanodine receptor Ca²⁺/K⁺ release tetrameric channel, RyR1, present in skeletal muscle, is 5038 aas long. Mutants are linked to core myopathies such as Central Core Disease and Multiple Minicore Disease) (Xu et al., 2008). RyR1 interacts with CLIC2 to modulate its channel activity (Meng et al., 2009).

Animals

RyR1 of Homo sapiens (P21817)

Insects

RyRi of Anopheles gambiae (Q7PMK5)

Animals

Brain IP₃-CaC of Rattus norvegicus

Animals

InsP3l receptor Drosophila melanogaster (P29993)

Ciliates

InsP3-like protein of Tetrahymena themophila (Q23K98)

Ciliates

InsP3l receptor of Paramecium tetraaurelia (A0CX44)

Inositol 1,4,5-triphosphate receptor type 1 splice variant, IP(3)R1 (Subedi et al., 2012)

Animals

IP(3)R1 of Rattus norvegicus (Q63269)

The flagellar motor (smf-dependent) (PomAB; MotXY) (Okabe et al., 2005)

Bacteria

PomAB/MotXY of Vibrio alginolyticus
PomA (O06873)
PomB (O06874)
MotX (BAB63401)
MotY (BAA12313)

The flagellar motor (pmf-dependent) (MotAB) (Ito et al., 2004)

Bacteria

MotAB of Bacillus subtilis
MotA (P28611)
MotB (P28612)

The flagellar motor (smf-dependent) (MotPS) (Ito et al., 2004)

Bacteria

MotPS (YtxDE) of Bacillus subtilis
MotP (YtxD) (MotA homologue) (P39063)
MotS (YtxE) (MotB homologue) (P39064)

The H⁺-driven flagellar motor complex, MotABXY (MotXY are required for systems 1.A.30.1.5 and 1.A.30.1.6; Koerdt et al., 2009).

Bacteria

The H⁺-driven flagellar motor complex of Shewanella oneidensis
MotA (Q8E9J0)
MotB (Q8E9J1)
MotX (Q8EAG6)
MotY (D4ZJA6)

The Na⁺-driven flagellar motor complex, PomAB MotXY (MotXY are required for systems 1.A.30.1.5 and 1.A.30.1.6; Koerdt et al., 2009)

Bacteria

The Na⁺-driven flagellar motor complex of Shewanella oneidensis
PomA (Q8EGR6)
PomB (Q8EGR5)
MotX (Q8EAG6)
MotY (D4ZJA6)

The TonB energy-transducing system. ExbB/D (the putative H⁺ channel) are listed here; TonB is listed under TC# 2.C.1.1.1.

Gram-negative bacteria

The TonB system of E. coli
ExbB (P0ABU7)
ExbD (P0ABV2) 

The TolA energy-transducing system. TolQ/R (the putative H⁺ channel) are listed here; TolA is listed under TC# 2.C.1.2.1, together with its auxiliary proteins. The channel is lined by TolR-Asp23, TolQ-Thr145 and TolQ-Thr178.

Gram-negative bacteria

The TolA system of E. coli
TolQ (P0ABU9)
TolR (P0ABV8) 

Putative TolA Energizer, TolQ1/TolR1

Proteobacteria

TolQ1/R1 of Myxococcus xanthus
TolQ1 (Q1DFL7)
TolR1 (Q1DFL8)

Putative TolA Energizer, TolQ2/TolR2

Proteobacteria

TolQ2/R2 of Myxococcus xanthus
TolQ2 (Q1D3D8)
TolR2 (Q1D3D7)

Putative TolA Energizer, TolQ3/TolR3

Proteobacteria

TolQ3/R3 of Myxococcus xanthus
TolQ3 (Q1CYB8)
TolR3 (Q1CYB7)

Putative TolA Energizer, TolQ4/TolR4

Proteobacteria

TolQ4/R4 of Myxococcus xanthus
TolQ4 (Q1DE42)
TolR4 (Q1DE41)

Putative TolA-dependent Energizer, TolQ5/TolR5 or AglX/AglV.  Identified as an essential motor for adventurous gliding motility (Nan et al. 2011).

Proteobacteria

TolQ5/R5 or AglX/AglV of Myxococcus xanthus
TolQ5 (Q1D0D3)
TolR5 (Q1D0D2)

TolQ (DUF2149)/TolR

δ-Proteobacteria

TolQ/TolR of Geobacter sp. M18
TolQ
TolR

Motor for adventurous motility, AglR (a TolQ homologue)/AglS (a TolR homologue) (Nan et al. 2011).

δ-Proteobacteria

AglQ/AglR of Myxobacter xanthus

Annexin A1 (McNeil et al., 2006)

Animals, plants, fungi, eukaryotic protists

Annexin A1 of Homo sapiens (346 aas; P04083)

Annexin 2 (forms a tetrameric complex with the S100A10 protein and binds the C-terminus of the AHNAK protein via the N-terminus of annexin 2 (De Seranno et al., 2006)

Animals

Annexin 2 of Homo sapiens (5890 aas; Q09666)

The Bacillus SpoIIQ/SpoIIIAH transcompartment channel

Bacteria

The SpoIIQ/SpoIIIAH complex of Bacillus subtilis
SpoIIQ (P71044)
SpoIIIAH (P49785)

Magnesium transport protein CorA

Bacteria

CorA of Bacillus subtilis

Putative metal ion transporter C27B12.12c

C27B12.12c of Schizosaccharomyces pombe

YfjQ of Bacillus subtilis

Zn²⁺/Cd²⁺ efflux system, ZntB. Mg²⁺ is not transported.

Bacteria

ZntB of Salmonella enterica serovar typhimurium

The ZntB Zn²⁺/Cd²⁺ transporter. The 1.9Å structure of the N-terminal cytoplasmic domain of ZntB has been solved (Tan et al., 2009).

Bacteria

ZntB of Vibrio parahaemolyticus (Q87M69)

High affinity root Mg²⁺ transporter, Mrs2/MGT1.  Plants have up to 10 Mrs2 homologues, and they can form homo as well as heterooligomeric channels (Schmitz et al. 2013).

Plants

Mrs2 of Arabidposis thaliana (Q9SAH0)

Magnesium transporter MRS2-11, chloroplastic (Magnesium Transporter 10) (AtMGT10)

Plants

MGT10 of Arabidopsis thaliana

The intracellular chloride channel (Mid1-related chloride [anion] channel, MCLC)

Animals

MCLC of Homo sapiens

CLIC- homologue

Animals

CLIC homologue of Nematostella vectensis

Clic-like Chloride channel protein 1

Animals

Clic-like protein of Acromyrmex echinatior (Panamanian leafcutter ant) (Acromyrmex octospinosus echinatior)

Putative chloride channel

Viruses

Chloride channel of Abalone herpesvirus Victorial

OOC-3 protein, isoform B.  Required for establishment of cortical domains in C. elegans embryos (Basham and Rose 1999; Pichler et al. 2000).

Animals

OOC-3 of Caenorhabditis elegans

Uncharacterized protein

Nematodes

Uncharacterized protein of Loa loa

Membrane-spanning 4 TMS subfamily A member 10 (MS4A superfamily), HTm4

Animals

HTm4 of Homo sapiens (Q96PG2)

4 TMS testes development-related NYD-SP21 protein

Animals

NYD-SP21 of Homo sapiens (Q96JA4)

The golgi pH regulator, GPHR

Animals

GPHR of Cricetulus griseus (B2ZXD5)

10 TMS homologue (826 aas)

Euglenozoa

10 TMS homologue of Leishmania mexicana (E9AL43)

4-5 TMS homologue (398 aas)

Alveolata

4-5 TMS homologue of Plasmodium yoelii (Q7RQA4)

Transient receptor potential (TRP) protein.  Assembles in vivo as homomultimeric channes, not as heteromeric channels with TrpL as had been reported (Katz et al. 2013).

Animals

TRP protein of Drosophila melanogaster (P19334)

Animals

TRPC1 of Homo sapiens (P48995)

Sperm TRP-3 (SPE-41) Ca²⁺-permeable channel. Translocated from vesicles to the plasma membrane upon sperm activation in a process dependent on the 4TMS SPE-38 protein (8.A.36.1.1) (Singaravelu et al., 2012) during sperm-egg interactions leading to fertilization (Xu et al., 2003).

Animals

TRP-3 of Caenorhabditis elegans (AAQ22724)

Short transient receptor channel 5 (TrpC5 or Htrp5) (transports Ca²⁺ and Sr²⁺ in the presence of Orai1 and STIM1 (TC# 1.A.52.1.1) (Ma et al., 2008). It is a cold-transducer in the peripheral nervous system (Zimmermann et al., 2011).

Animals

TrpC5 of Homo sapiens (Q9UL62)

TrpL (Trp-like), isoform A (1124 aas).  Assembles in vivo as homomultimeric channes, not as heteromeric channels with Trp as had been reported (Katz et al. 2013).

Animals

TrpL of Drosophila melanogaster (P48994)

TRP-like ion channel

Yeast

TRP-like channel protein of Schizosaccharomyes pombe (O94543)

Vanilloid receptor subtype 1 (VR1 or TRPV1) (noxious, heat-sensitive [>42°C]; also sensitive to acidic pH and voltage; serves as the receptor for the alkaloid irritant, capsaicin, and for resiniferatoxin; regulated by bradykinin and prostaglandin E2) (contains a C-terminal region, adjacent to the channel gate, that determines the coupling of stimulus sensing and channel opening (Garcia-Sanz et al., 2007; Matta and Ahern, 2007). Activated and sensitized by local anesthetics in sensory neurons (Leffler et al., 2008). A bivalent tarantula toxin activates the capsaicin receptor (TRPV1) by targeting the outer pore domain (Bohlen et al., 2010). Single-channel properties of TRPV1 are modulated by phosphorylation (Studer and McNaughton, 2010). TRPV1 mediates an itch associated response (Kim et al., 2011). The thermosensitive TRP channel pore turret is part of the temperature activation apparatus (Yang et al., 2010). Modular thermal sensors in temperature-gated transient receptor potential (TRP) channels have been identified (Yao et al., 2011).

Animals

VR1 of Rattus norvegicus

Stretch-inhibitable non-selective cation channel, SIC

Animals

SIC of Rattus norvegicus

Vanilloid receptor-related, osmotically activated channel, VR-OAC (also called TRPV4 and Trp12); required for bladder voiding in mice (Gevaert et al., 2007). Regulated by Pacsin3 via its SH3 domain which affects its subcellular localization and inhibits its activity in a stimulus-specific fashion (D'hoedt et al., 2008). Responsible for autosomal dominant brachyolmia (Rock et al., 2008). Multiple gating mechanisms have been demonstrated for TRPV4 (Loukin et al., 2010). TRPV4 Ca²⁺ signalling regulates endothelial vascular function (Sonkusare et al., 2012).

Animals

VR-OAC of Rattus norvegicus

Intestinal endocyte Ca²⁺ (Sr²⁺; Ba²⁺) entry channel, CaT1. Excision of the Trpv6 gene leads to severe defects in epididymal Ca²⁺ absorption and male fertility as does the single D541A pore mutation (Weissgerber et al., 2012).

Animals

CaT1 of Rattus norvegicus

The noxious heat (>52°C)-sensitive vanilloid-like receptor cation selective channel, TRPV2. Ca²⁺-dependent desensitization of TRPV2 channels is mediated by hydrolysis of phosphatidylinositol 4,5-bisphosphate (Mercado et al., 2010).

Animals

TRPV2 of Homo sapiens

Vacuolar, voltage-dependent cation-selective, Ca²⁺-activated channel, YVC1. (Yeast vacuolar conductance protein 1; also called TrpY1; Yor088w) (Chang et al., 2009). Activated by stretch to release vacuolar Ca²⁺ into the cytoplasm upon osmotic upshock. (Activated by glucose, indole and other aromatic compounds (Haynes et al., 2008; Groppi et al. 2011)).

Yeast

YVC1 (Yor088w) of Saccharomyces cerevisiae (Q12324)

Melastatin 1 (a non-selective, Ca²⁺-permeable cation channel, implicated in cell death (Wilkinson et al., 2008).

Animals

Melastatin 1 of Homo sapiens

Ca²⁺-activated nonselective cation (Na⁺ and K⁺) channel (non-permeable to Ca²⁺), TRPM4b. Forms a protein-protein interaction with the TRPC3 channel and suppresses store-operated Ca⁺ entry (Park et al., 2008).  Contributes to the mammalian atrial action potential (Simard et al. 2013).

Animals

TRPM4b of Homo sapiens

ADP-ribose/NAD/pyrimidine nucleotide-gated Ca²⁺ permeable, cation nonselective, long transient receptor potential channel-2, LTRPC2; Melastatin 2; TRPM2 (ATP inhibitable). The 3-D structure resembles a swollen bell shaped structure (Maruyama et al., 2007). Can be converted to an anion selective channel by introducing a lysyl residue in TMS 6 (Kuhn et al., 2007). Transports Ca²⁺ and Mg²⁺ with equal facility (Xia et al., 2008).  Four Ca²⁺ ions activate TRPM2 channels by binding in deep crevices near the pore but intracellularly of the gate (Csanády and Törocsik, 2009). Protons also regulate activity (Starkus et al., 2010). Present in the plasma membrane and lysosomes; plays a role in ROS-induced inflammatory processes and cell death. Melastatin is required for innate immunity against Listeria monocytogenes (Knowles et al., 2011). Functions in pathogen-evoked phagocyte activation, postischemic neuronal apoptosis, and glucose-evoked insulin secretion, by linking these cellular responses to oxidative stress (Tóth and Csanády, 2012).  Pore collapse upon prolonged sto,i;atopm imderlies irreversible inactivation (Tóth and Csanády 2012).

Animals

LTRPC2 of Homo sapiens

Transient receptor potential cation channel subfamily, member 3. Activated by muscarinic receptor activation.

Animals

TrpM3 of Homo sapiens (Q9HCF6)

Cold-sensitive (<22°C) and menthol-sensitive cation-selective channel, TRPM8. TRPM8 is activated by low temperatures and cooling agents such as menthol. It underlies the cold-induced excitation of sensory neurons. Its gating is regulated by voltage and lysophospholipids which induce prolonged channel opening (Vanden Abeele et al., 2006; Bautista et al., 2007; Matta and Ahern, 2007). Can be converted to an anion selective channel by introducing a lysyl residue in TMS 6 (Kuhn et al., 2007). Gating of transient receptor potential melastatin 8 (TRPM8) channels is activated by cold and chemical agonists in planar lipid bilayers (Zakharian et al., 2010).

Animals

TPM8 of Homo sapiens

The intestinal/renal Mg²⁺ absorption Mg²⁺ influx channel, Melastatin6 or TRPM6 (5x higher affinity for Mg²⁺ than Ca²⁺; regulated by internal Mg²⁺) (Voets et al., 2004). TRPM6 and its closest homologue TRPM7 (also a Mg²⁺-permeable cation channel) assemble to form a functional heterooligomeric channel (Chubanov et al., 2004) (mutations in TRPM6 promotes hypomagnesemia with secondary hypocalcemia) (Chubanov et al., 2007). TRPM6 and the closely related TRPM7 are large channel-kinase proteins (Li et al., 2007; Schmitz et al., 2007). TRPM7 also transports protons competitively with Mg²⁺ and Ca²⁺ (Numata and Okada, 2008). Intracellular ATP regulates TRPM6 channel activity via its α-kinase domain independently of α-kinase activity (Thébault et al., 2008). Also plays a role in Zn²⁺ homeostasis and Zn²⁺- mediated neuronal injury (Inoue et al., 2010).

Animals

TRPM6 of Homo sapiens (NP_060132)
TRPM7 of Homo sapiens (TC #1.A.4.5.1)

Transient receptor potential cation channel TrpM

T9.a.14.4.12

rpM of Drosophila melanogaster

Cold-activated cation channel in nociceptive sensory neurons, ANKTM1, with lower activation temperature (in the noxious cold range) than TRPM8 (TC #1.A.4.5.7) (Story et al., 2003). Also called TRPA1 (Acc #AAS78661) which translates sound into electric signals in the ear. It sits at the tips of cilia in the inner ear and allows passage of K⁺ and Ca²⁺ into the cell. Vibrations in the hair cause the channel to open and close. The frequency of the sound waves generate an electrical signal of the same frequency (Jordt et al., 2004). (Shows 25% identity with α-latrotoxin precursor (TC #1.C.6.3.1.1) in its N-terminal half.) TRPA1 is a polyunsaturated fatty acid sensor in mammals, but not in flies and fish (Motter and Ahern, 2012). TRPA1 is regulated by its N-terminal ankyrin repeat domain (Zayats et al., 2012).

Animals

ANKTM1 of Mus musculus (Q8BLA8)

The nociceptive neuron TRPA1 that senses peripheral damage by transmitting pain signals (activated by cold temperatures, pungent compounds and environmental irritants). Noxious compounds also activate through covalent modification of cysteyl residues (Macpherson et al., 2007). TRPA1 is an excitatory, nonselective cation channel implicated in somatosensory function, pain, and neurogenic inflammation. Through covalent modification of cysteine and lysine residues, TRPA1 can be activated by electrophilic compounds, including active ingredients of pungent natural products (e.g., allyl isothiocyanate), environmental irritants (e.g., acrolein), and endogenous ligands (4-hydroxynonenal) (Chen et al., 2008). General anesthetics activate TRPA1 nociceptive ion channels to enhance pain and inflammation (Matta et al., 2008; Leffler et al., 2011). TMS5 is a critical molecular determinant of menthol sensitivity (Xiao et al., 2008). TRPA1 is a component of the nociceptive response to CO₂ (Wang et al., 2010). TRPA1 is a polyunsaturated fatty acid sensor in mammals but not in flies and fish (Motter and Ahern, 2012). TRPA1 is regulated by its N-terminal ankyrin repeat domain (Zayats et al., 2012).  Mutations in TrpA1 cause alterred pain perception (Kremeyer et al. 2010).

Animals

TRPA1 of Homo sapiens (O75762)

The pore forming subunit, Trp-4, a mechanosensitive channel. Present in ciliated mechanosensitive neurons; Activation and latency occur in the microsecond range. trp-4 mutations alter ion selectivity (Kang et al., 2010). 

Animals

Trp-4 of Caenorhabditis elegans (Q9GRV5)

Yeast

TRP-like ion channel Pkd2 (Polycystic kidney disease-related ion channel 2).  Regulates cytoplasmic calcium ion concentrations (Ma et al. 2011).

Yeast

Pkd2 of Schizosaccharomyces pombe

Flc2p

Yeast

Flc2 of Saccharomyces cerevisiae

The ion channel protein, Vpu. The mutation A18H converts a non-specific channel to a selective proton channel that is sensitive to rimantadine (Sharma et al., 2011).

Virus

The Vpu of HIV-1

Virus

Pb2 of phage T5 (Q7Y5E2)

Phage (Virus)

DNA/protein translocase of phage P22
gp7 (Q01074)
gp16 (Q01146)
gp20 (Q01076)

Bestrophin-1 anion channel; VMD2 gene product (NO₃^- > I^- > Br^- > Cl^-; P_NO3^-/P_Cl^- = 5.8) (Sun et al., 2002). Regulated by ceramide-induced dephosphorylation (Xiao et al., 2009).

Animals, plants, fungi, bacteria

Bestrophin-1 of Homo sapiens (O76090)

Bestrophin-2 anion channel (P_NO3^-/P_Cl^- = 2.7) (Sun et al., 2002).  The mouse orthologue is swell-insensitive, but the first 64 aas of Bestrophin 1 of Drosophila melanogaster allowed it to mediate cell swelling in response to hypo-osmotic stress (Stotz and Clapham 2012).

Animals, plants, fungi, bacteria

Bestrophin-2 of Homo sapiens (AAM76995)

Animals

Best3 of Mus musculus
(Q6H1V1)

Bestrophin1, isoform B.  Identified as the Cl^- (swell) channel that allows swelling in hypo-osmotic solutions (Stotz and Clapham 2012).  Its N-terminal 64 aas are essential for swell activation. 

Animals

Bestrophin1 of Drosophila melanogaster (B7Z0U6)

Plasma membrane Ca²⁺-activated anion-selective channel, Best1 (AN2251) (transports citrate, propionate, benzoate, and sorbate) (Roberts et al., 2011).

Fungi

Best1 of Aspergillus nidulans (Q5BB29)

Fungal Best2 protein, AN6909 (Roberts et al., 2011) (29% identical to Best1 (TC# 1.A.46.2.1)).

Fungi

Best2 of Aspergillus nidulans (Q5AXS1)

Bestrophin homologue 

Cyanobacteria

Bestrophin homologue of Cyanothece sp. PCC8801 (B7K217)

Bestrophin homologue

Firmicutes

Bestrophin homologue of Bacillus cereus (C2UY63)

Bestrophin homologue 

δ-Proteobacteria

Bestrophin homologue of Bdellovibrio bacteriovorus (Q6MLK6)

Bestrophin homologue, YneE 

γ-Proteobacterium

YneE of E. coli (B2N0W4)

Bestrophin homologue

Plants

Bestrophin homologue of Arabidopsis thaliana (Q9M2D2)

TTYH1 maxi-Cl^- anion channel

Animals & plants

Tweety homologue 1 (TTYH1) of Homo sapiens (Q9H313)

MICC of Bos taurus (Q9T2U8)

Polycystin 1 (PKD1) assembles with TRPP2 (Q86VP3) in a stoichiometry of 3TRPP2: 1PKD1, forming the receptor/ion channel complex (Yu et al., 2009). The C-terminal coiled-coil complex is critical for proper assembly (Zhu et al., 2011).  Missense mutation have been identified that affect membrane topogenesis (Nims et al. 2011).

Animals

Polycystin 1 of Homo sapiens

Polycystic kidney disease protein 1-like 3 (PC1-like 3 protein or PKD1L3) (Polycystin-1L3).  May particpate in formation of the TRP sour taste receptor (see 1.A.5.2.2) (Ishimaru et al. 2010).

Animals

PKD1L3 of Homo sapiens

Polycystin 2 (PKD2) (Anyatonwu and Ehrlich, 2005). Regulated by α-actinin (AAC17470) by direct binding (Li et al., 2007). Regulated by diaphanous-related formin 1 (mDia1) (Bai et al., 2008). Has 6 TMSs with N- and C- termini inside (Hoffmeister et al., 2010).

Animals

Polycystin 2 of Homo sapiens (Q13563)

Polycystic kidney disease Z-like protein, TrpP3 or PKD2L1 (50% identical to Polycystin 2 (1.A.5.2.1); regulated by α-actinin (AAC17470) by direct binding; Li et al, 2007). May form a heterodimeric complex with PKD1L3 (1.A.5.1.2) to form the TRP sour taste channel receptor (Ishimaru et al., 2006; Ishimaru et al. 2010).

Animals

TrpP3 of Mus musculus (Q14B55)

Pkd-2 of Caenorhabditis elegans

Animals

TRP-ML1 (Mucolipin-1) of Homo sapiens (Q9GZU1)

The TRP-ML3 (Mucolipin-3) inward rectifying cation channel; associated with the mouse Viartini-Waddler phenotype when mutant (A419P) (Kim et al., 2007). H⁺-regulated Ca²⁺ channel that shuttles between intracellular vesicular compartments and the plasma membrane (Kim et al., 2010).

Animals

Trp-ML3 of Mus musculus
(Q8R4F0)

Mucolipin-2 (TRPML2) non-selective plasma membrane cation channel (Ca2+ permeable). Shows inward rectification like TRPML1 and TRPML3 (Lev et al., 2010). Induces cell degeneration. Causes embryonic lethality, pigmentation defects, and deafness and regulates the acidification of early endosomes (Noben-Trauth, 2011). Found in the plasmamembrane and early- and late-endosomes as well as lysosomes.

Animals

TRPML2 of Homo sapiens (Q8IZK6)

Sarcolipin (SLN). Oligomeric interactions of sarcolipin and the Ca-ATPase have been documented (Autry et al., 2011).  Sarcolipin, but not phospholamban, promotes uncoupling of the SERCA pump (3.A.3.2.7; Sahoo et al. 2013)

Animals

SLN of Homo sapiens (O00631)

The voltage-gated proton channel, H_v1 or HVCN1 (273 aas) (Ramsey et al., 2006). Thr29 is a phosphorylation site that activates the HVCN1 channel in leukocytes (Musset et al., 2010).

Animals

H_v1 of Homo sapiens (Q96D96)

Voltage-gated proton channel, HvCN1; VSOP; VSX1 (Sasaki et al., 2006) exhibits pH-dependent gating and Zn²⁺-reactivity.

Animals

HvCN1 of Ciona intestinalis (Q1JV40)

Voltage-gated proton-specific monomeric channel, kHv1. Activated by depolarization; functions in signaling and excitability to trigger bioluminescence (Smith et al., 2011).  Hv1 most likely forms an internal water wire for selective proton transfer, and interactions between water molecules and S4 arginines may underlie coupling between voltage- and pH-gradient sensing (Ramsey et al. 2010).

Dinoflagellates

kHv1 of Karlodinium veneficum (G5CPN9)

The CRAC channel protein, Orai1, complexed with the STIM1 protein (Feske et al., 2006). The Orai1: Stim stoichiometry = 4:2 (Ji et al., 2008). Human Orai1 and Orai3 channels are dimeric in the closed resting state and open states. They are tetrameric when complexed with STIM1 (Demuro et al., 2011). A dimeric form catalyzes nonselective cation conductance in the STIM1-independent mode.  STIM1 domains have been characterized (How et al. 2013).

Animals

Orai1/STIM1 complex of Homo sapiens
Orai1 (Q96D31)
STIM1 (Q13586)

The ARC (Arachidonate-regulated Ca²⁺-selective) channel, a complex of STIM1, Orai1 and Orai3 (Mignen et al., 2008). It is a heteropentameric assembly of three Orai1 subunits and two Orai3 subunits (Mignen et al., 2009). (But see Demuro et al., 2011; 1.A.52.1.1). Molecular determinants within the N-terminus control channel activation and gating (Bergsmann et al., 2011).

Animals

Orai3 of Homo sapiens (Q9BRQ5)

The CRAC channel Orai2 (DUF 1650) (264 aas) (Gross et al., 2007).

Animals

Orai2 of Mus musculus (Q8BH10)

Insect STIM1/Orai1 (Hull et al., 2010). Influences sex pheromone production in moths. 

Animals

Stim1/Orai1A or B of Bombyx mori 
Stim1 (B5BRC2)
Orai1, splice form A (B5BRC5)
Orai1, splice form B (B5BRC4) 

Orai homologue (494aas; 4 or 5 TMSs)

Plants

Orai homologue in Ostreococcus tauri (Q012G5)

Orai homologue (244aas; 4 TMSs)

Stramenophiles

Orai homologue in Phytophthora infestans T30-4 (D0NKP9)

Animals

Presenilin-1 of Homo sapiens (467 aas; P49768)

Archaeal presenilin homologue (DUF1119; COG3389; PSN). Members of the peptidase A22B superfamily (found in many archaea, but not bacteria, shows some sequence similarity to members of the LIV-E family, e.g., 2.A.78.2.1))

Archaea

PSN of Haloquadratum walsbyi (339 aas; 9 TMSs; CAJ51633)

Signal peptide peptidase-2A (SPP2A; 523 aas; 8TMSs) (no evidence for a transport function).

Animals

SPP2A of Mus musculus (Q9JJF9)

Signal peptide peptidase like 2A, SPPL2A

Animals

SPPL2A of Homo sapiens

Signal peptide peptidase, Spp

Animals

Spp of Homo sapiens

Signal peptide peptidase, Spp

Animals

Spp of Drosophila melanogaster

Mammalian Ca²⁺ channel, Flower, homologue, isoform a (Yao et al., 2009).

Animals

Flower of Homo sapiens (Q9UGQ2)

Insect Ca²⁺ channel, Flower (194 aas; 4 putative TMSs)

Animals

Flower of Drosophila melanogaster (Q95T12)

Roundworm Flower homologue (166aas)

Animals

Flower homologue of Caenorhabditis elegans (Q93533)

Flatworm Flower homologue (195aas)

Animals

Flower homologue of Schistosoma japonicum (Q5DFV8)

Fungal flower homologue (149aas)

Fungi

Flower homologue of Aspergillus flavus (B8N1Q6)

Copper uptake system, COPT6. Interacts with itself and its homolog, COPT1. Regulated by copper availability by using SPL7 (Jung et al., 2012). 

Plants

COPT6 of Arabidopsis thaliana (Q8GWP3)

Copper transporter, PF14_0369 (Choveaux et al. 2012). Binds Cu⁺ and is present in both the erythrocyte and parasite plasma membranes (Choveaux et al. 2012).

Alveolata

Copper transporter of Plasmodium falciparum

Ferric chelate reductase (N-terminus;5 TMSs; TC# 5.B.2) fused to a Ctr copper transporter (C-terminus; 3 TMSs).

algae

Ctr fusion protein of Galdieria sulphuraria

Grape vacuolar copper transporter, Ctr1 (Martins et al. 2012).

Plants

Ctr1 of Vitis vinifera

Copper (Cu⁺) and possibly silver (Ag⁺) uptake transporter (trimeric; Eisses and Kaplan, 2005).(Forms an oligomeric pore with each subunit displaying 3 TMSs and 2 metal binding motifs (Lee et al., 2007)). (Mediates basolateral uptakes of Cu⁺ in enterocytes (Zimnicka et al., 2007)). Human Ctr1 shows copper-dependent internalization and recycling which provides a reversible mechanism for the regulation of cellular copper entry (Molloy and Kaplan, 2009). Ctrl acts as a receptor for the two extinct viruses, CERV1 and CERV2 (Soll et al., 2010). Ctrl takes up platinum anticancer drugs, cisplatin and carboplatin (Du et al., 2012). The 3-d structure is known (Yang et al., 2012).  Has a low turn over number of about 10 ions/second/trimer (Maryon et al. 2013).  Methionine and histidine revidues in the transmembrane domain are essential for transport of copper but when mutated stimulated uptake of cisplatin (Larson et al. 2010).

Animals

SLC31A1 of Homo sapiens

The heterodimeric copper uptake transporter, Ctr4/Ctr5. The Ctr4 central domain may mediate Cu transport in this hetero-complex, whereas the Ctr5 carboxyl-terminal domain functions in the regulation of trafficking of the Cu transport complex to the cell surface (Beaudoin et al., 2011).

Yeast

Ctr4/Ctr5 of Schizosaccharomyces pombe
Ctr4
Ctr5

Green algae

Ctr1 of Chlamydomonas reinhardtii (Q4U0V9)

SARS-CoV Viroporin tetrameric ion channel. Protein 3a is of 274 aas and 3 TMSs.

Animal Viruses

SARS-Caronavirus
Viroporin
(Protein 3a)
(P59632)

Orf3 of 249aas and 3 putative TMSs

Viruses

Orf3 of Zaria bat coronavirus (F1BYM0)

The NS3 protein of 230aas and 3 N-terminal TMSs as well as 3 potential C-terminal TMSs of low hydrophobicity.

Viruses

NS3 of Bat coronavirus HKU9-5-1 (E0ZN37)

Orf3 of 238aas and 3 putative TMSs

Viruses

Orf3 of Eidolon bat coronavirus (F1DAZ2)

The Matrix protein BM2 (Pielak and Chou, 2010).

Viruses

BM2 influenza virus type B
(P03493)

The pore-forming peptide, Pep46 (derived from the structural polyprotein (PP) precursor (1012 aas). The 3-D NMR structure of Pep 46: Acc# 2IMUA. 

Viruses

PP precursor of Pep46 of Infectious Bursal Disease Virus (P61825)

Epithelial Na⁺ channel, ENaC (regulates salt and fluid homeostasis and blood pressure; regulated by Nedd4 isoforms and SGK1, 2 and 3 kinases) (Henry et al., 2003; Pao 2012).  Cd²⁺ inhibits α-ENaC by binding to the internal pore where it interacts with residues in TMS2 (Takeda et al., 2007).  The channel is regulated by palmitoylation of the beta subunit which modulates gating (Mueller et al. 2010).

Animals

α₂βγ ENaC heterotetrameric epithelial Na⁺ channel of Homo sapiens

Amiloride-sensitive cation channel, ASIC3 (also called BNC1 or MDEG) which is an acid-sensitive (proton-gated) homo- or hetero-oligomeric cation (Na⁺ (high affinity), Ca²⁺, K⁺) channel. It associates with DRASIC and ASIC1. It mediates touch sensation, being a mechanosensor) (lead inhibited) (Wang et al., 2006). In pulmonary tissue (lung epithelial cells) it and CFTR interregulate each other (Su et al., 2006). ASIC3 is a sensor of acidic and primary inflammatory pain (Deval et al., 2008).

Animals

αβγENaC of Rattus norvegicus.
DRASIC (O35240)
ASIC3 (O55163)
ASIC1 (P55926)

The epithelial Na⁺ channel, EnaC5 (involved in fluid and electrolyte homeostasis). The C-terminus of each subunit (α, β, and γ) contains a PPXY motif for interaction with the WW domains of the ubiquitin-protein ligases, Nedd4 and Nedd4-2. Disruption of this interaction, as in Liddle's syndrome where mutations delete or alter the PPXY motif of either the β or γ subunits, has been shown to result in increased ENaC activity and arterial hypertension. N4WBP5A (Nedd4-family interacting protein-2) plays a role (see 8.A.30; Konstas et al., 2002). Wiemuth & Grunder (2010) showed that an unknown ligand, interacting with an amino acyl residue in the extracellular domain, tunes Ca²⁺ inhibition in the rat protein, but not the mouse orthologue.

Animals

ENaC5 of Rattus norvegicus (Q9R0W5)

animal

ACD-1 of Caenorhabditis elegans (P91102)

Neuronal acid-sensing cation channel-1, ASIC1 (>90% identical to ASIC1 of Rat (TC#1.A.6.1.2)). 3D structure (1.9Å resolution) has been solved (Jasti et al., 2007). Regulated by the glucocorticoid-induced kinase-1 isoform 1 (SGK1.1) (Arteaga et al., 2008). Residues in the second transmembrane domain of the ASIC1a that contribute to ion selectivity have been defined (Carattino and Della Vecchia, 2012). Outlines of the pore in open and closed conformations describe the gating mechanism (Li et al., 2011). Interactions between two extracellular linker regions control sustained channel opening (Springauf et al., 2011).

Animals

ASIC-1 of Gallus gallus (Q1XA76)

Amiloride and acid-sensitive cation channel, ASIC2. Acid sensing ion channel-1b (ASIC1b or ASIC2) (stimulated by hypotonic stimuli; Ugawa et al., 2007;Deval et al., 2008) (like 1.A.6.1.2)

Animals

ASIC1b of Mus musculus (Q925H0)

ASIC1b or ASIC2 of Rattus norvegicus (Q62902)

Touch-responsive mechanosensitive degenerin channel complex (Mec-4/Mec-10 form the channel; Mec-2 and Mec-6 activate) (Bianchi, 2007; Chelur et al., 2002)

Worm

Mec-2, 4, 6, 10 mechanosensitive degenerin channel complex in Caenorhabditis elegans
Mec-4
Mec-10
Mec-6
Mec-2

Animals

UNC-105 of Caenorhabditis elegans (Q09274)

Mechanotransduction degenerin, DEL-1 (Bianchi, 2007).

Animals

DEL-1 of Caenorhabditis elegans (Q19038)

Serum paraoxonase/arylesterase 1, PON 1 (Aromatic esterase 1) (A-esterase 1) (Serum aryldialkylphosphatase 1)

Animals

PON1 of Homo sapiens

FMRFamide-gated  sodium channel, FaNaC.  Aspartate 552 in TMS2 influcences the gating properties and potency of the channel (Kodani and Furukawa 2010).

Animals

FaNaC of Aplysia kurodai

Ripped pocket (Rpk) fly gonad-specific Na⁺ channel (amiloride-sensitive) (Adams et al., 1998).

Animals

Rpk of Drosophila melanogaster

Pickpocket (Adams et al., 1998; Zhong et al., 2010).

Animals

Pickpocket of Drosophila melanogaster (Q7KT94)

Putative Na⁺ channel 

Animals

Putative Na⁺ channel of Drosophila melanogaster (O61365)

FMRFamide (peptide)-gated ionotropic receptor Na⁺ channel, NaC2-4 or NaC2, 3 and 5 (gated by neuropeptides Hydra-RFamides I and II; present in tentacles) (Golubovic et al. 2007). Three homologous subunits, NaC2, 3 and 5, assemble to form a more typical high affinity peptide-gated ion channel (Durrnagel et al., 2010).

Cniderians

NaC2-5 of Hydra magnipapillata:
NaC2 - A8DZR6
NaC3 - A8DZR7
NaC4 - A8DZR8
NaC5 - D3UD58

Core protein Mu-1 (42aas; 1TMS) (Agosto et al., 2006). The reovirus myristoylated µ1N pore forming peptide derived from the N-terminus of the µ1 viral capsid protein (708aas). Permeability order: Cs⁺ > Rb⁺ > K⁺ > Na⁺ > Li⁺ (crystal structures are available for chains A-U).

Viruses

Mu-1 of mammalian reovirus (P12397)

Bacterial TRIC family homologue

Bacteria

TRIC homologue of Gramella forsetii (A0M015)

Archaeal TRIC family homologue

Archaea

TRIC homologue of Sulfolobus solfataricus (Q981D4)

Putative TRIC channel protein

Algae

Putative TRIC channel of Galdieria sulphuraria

Putative TRIC channel protein

Stramenopiles

Putative TRIC channel of Blastocystis hominis

Putative TRIC channel protein

Amoeba

Putative TRIC channel protein of Acanthamoeba castellanii

Myelin and Lymphocyte Protein, MAL/VIP17 protein, a regulator of NKCC2 (2.A.30.1.1). It stabilizes kidney apical membranes, and facilitates sorting of proteins to these membranes (Carmosino et al., 2010). Like plasmolipin, it has 4 TMSs that align with those of plasmolipin.

Mammals

MAL/VIP17 of Canis familiaris (Q28296)

Myeloid-associated differentiation marker, MyADM (322 aas; 8 TMSs) 

Animals

MyADM of Homo sapiens (Q96S97)

4 TMS MARVEL superfamily member

Animals

4TMS homologue of Caenorhabditis elegans (P83387)

CKLF-like MARVEL transmembrane domain-containing protein 7, CMTM7 (175aas; 4 TMSs; Miyazaki et al., 2012). CMTM7 functions to link sIgM and BLNK in the plasma membrane, to recruit BLNK to the vicinity of Syk, and to initiate BLNK-mediated signal transduction (Miyazaki et al., 2012). No transport function is known.

Animals

CMTM7 of Homo sapiens (Q96FZ5)

Proteolipid protein 2 (Differentiation-dependent protein A4) (Intestinal membrane A4 protein)

Animals

A4 protein of Homo sapiens