The plasma membrane Ca² -activated chloride (ICl_Ca) channel, TMEM16A (Anoctamin 1a; ANO1a; ANO1, DOG1, ORAOV2, TAOS2) (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).  The protein exists in the membrane as a homodimer where the cytoplasmic N-terminus functions in dimerization (Tien et al. 2013).  TMSs 5-6 of the 8 TMSs may comprise parts of the pore-loop that controls Cl^- conductance (Adomaviciene et al. 2013).  ANO1 confers ICl_Ca in retinal neurons and acts as an intrinsic regulator of the presynaptic membrane potential during synaptic transmission (Jeon et al. 2013).  TMEM16A may be a primary driver of the "Grow" (tumor proliferation) or "Go"(metastasis) model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation (Shiwarski et al. 2014).  Regulation of TMEM16A/16B by Ca²⁺ is mediated by preassociated apo-calmodulin (Yang et al. 2014) as well as CaMKIIδ (Gui et al. 2015).  Because the Cl^- channel is the only active ion-selective conductance with a reversal potential that lies within the dynamic range of spiral ganglion neurons (SGN) action potentials, developmental alteration of [Cl^-], and hence the equilibrium potential for Cl^- (ECl), transforms the pre- to the post-hearing phenotype (Zhang et al. 2015).  Four basic residues involved in ion selectivity and pore blocker sensitivity have been identified (Peters et al. 2015).  Channel activity is required for mucus secretion induced by interleukin-13 (Lin et al. 2015; Zhang et al. 2015). Ano1 may interact cooperatively with TrpV1 (TC# 1.A.4.2.1) to form a thermal sensor (Kanazawa and Matsumoto 2014). Inhibitors have been described (Boedtkjer et al. 2015).  The first intracellular loop serves as a Ca²⁺ binding site and includes D439, E444 and E447 (Pang et al. 2015).  It is inhibited by various 4-Aryl-2-amino thiazoles at concentrations as low as 1 mμM (Piechowicz et al. 2016).  ANO1 and TRPC6 (1.A.4.1.5) are present in the same macromolecular complex and localize in close spatial proximity in the myocyte plasma membrane.  TRPC6 channels probably generate a local intracellular Ca²⁺ signal that activates nearby ANO1 channels in myocytes to stimulate vasoconstriction (Wang et al. 2016).  ANO1 transports bicarbonate which functions in the regulation of pancreatic acinar cell pH (Han et al. 2016).  TMEM16A contains two ion conduction pores that are independently activated by Ca²⁺ binding to sites that are embedded within the transmembrane part of each subunit (Lim et al. 2016).  Interactions between the carboxy- terminus and the first intracellular loop in the TMEM16A homo-dimer regulate channel activity (Scudieri et al. 2016).  A STAT6-TMEM16A-ERK1/2 signal pathway and TMEM16A channel activity are required for the Interleukin-13 (IL-13)-induced TMEM16A-mediated mucus production (Qin et al. 2016). Angiotensin II elicits a TMEM16A-mediated current, and TMEM16A participates in Ang II-induced basilar constriction via the RhoA/ROCK signaling pathway (Li et al. 2016). 2-acylamino-cycloalkylthiophene-3-carboxylic acid arylamides (AACTs) are inhibitors of TMEM16A, and 48 synthesized analogs (10ab-10bw) of the original AACT compound (10aa) have been synthesized and studied.  The most potent compound (10bm), which contains an unusual bromodifluoroacetamide at the thiophene 2-position, had an IC50 ~ 30 nM (Truong et al. 2017).  Ano1 plays a role in asthma (Wang et al. 2017). The E143A mutant showed reduced sensitivity to Ca²⁺ but not to high temperatures, whereas the E705V mutant exhibited reduced sensitivity to both Ca²⁺ and noxious heat (Choi et al. 2018). Voltage modulation of TMEM16A involves voltage-dependent occupancy of calcium- and anion-binding site(s) within the membrane electric field as well as a voltage-dependent conformational change intrinsic to the channel protein. These gating modalities all critically depend on the sixth transmembrane segment (Peters et al. 2018). TMEM16A in myocytes plays a major functional role in contraction (Mohanakumar et al. 2018). Bile acids activate TMEM16A and thereby increase cholangiocyte fluid secretion (Li et al. 2018). TMEM16A participates in H₂O₂-induced apoptosis via modulation of mitochondrial membrane permeability (Zeng et al. 2018). Glioma-associate oncogene proteins, Gli1 and Gli2, bind to the promoter and repress ANO1 transcription, dependent on Gli binding to a site close to the ANO1 transcriptional start site (Mazzone et al. 2019). Clarithromycin suppresses IL-13-induced goblet cell metaplasia via the TMEM16A-dependent pathway in guinea pig airway epithelial cells (Hara et al. 2019).  TMEM16A is involved in gastric emptying, and TMEM16A inhibition may be effective in treating disorders of accelerated gastric emptying, such as dumping syndrome (Cil et al. 2019).  Phosphatidylinositol (4,5)-bisphosphate (PIP2) regulates TMEM16A channel activation and desensitization by binding to a binding site, possibly at the cytosolic interface of TMSs 3-5. The ion-conducting pore of TMEM16A consists of two functionally distinct modules: a Ca²⁺-binding module formed by TMSs 6-8 and a PIP2-binding regulatory module formed by TMs 3-5, which mediate channel activation and desensitization, respectively (Sui et al. 2020). TMEM16A plays a dual role in LPS-induced intestinal epithelial barrier dysfunction (Sui et al. 2020). Hepatocyte TMEM16A plays a role in nonalcoholic fatty liver disease (NAFLD), and its deletion retards NAFLD progression by ameliorating hepatic glucose metabolic disorder (Guo et al. 2020). Hepatocyte TMEM16A interacts with vesicle-associated membrane protein 3 (VAMP3) to induce its degradation, suppressing the formation of the VAMP3/syntaxin 4 and VAMP3/synaptosome-associated protein 23 complexes (see TC# 1.F.1.1.5). This leads to impairment of hepatic glucose transporter 2 (GLUT2) translocation and glucose uptake (Guo et al. 2020). TMEM16A is a potential biomarker for Lung Cancer (Hu et al. 2019). Allosteric modulation of alternatively spliced Ca²⁺-activated Cl^- channels, TMEM16A by PI(4,5)P2 and CaMKII (TC# 8.A.104.1.11) has been demonstrated (Ko et al. 2020). Signaling through the interleukin-4 and interleukin-13 receptor complexes regulates cholangiocyte TMEM16A expression and biliary secretion (Dutta et al. 2020). A second Ca²⁺ binding site allosterically controls TMEM16A activation (Le and Yang 2020). A long noncoding RNA (lncRNA), ANO1-AS2, downregulates the ANO1 gene by interacting with the ANO1 gene promoter, which can influence sperm motility and morphology (Saberiyan et al. 2020). Ano1 plays an important role in generating urethral tone (Drumm et al. 2021). Human TMEM16A shows increated expression in many cancers (Chen et al. 2021). TMEM16A is inhibitied by liquiritigenin (Kato et al. 2021) and is activated by the natural product canthaxanthin which  promotes gastrointestinal contraction (Ji et al. 2020). TMEM16A ameliorates vascular remodeling by suppressing autophagy via inhibiting Bcl-2-p62 complex formation. It regulates the four-way interaction between p62 (P37198; TC# 1.I.1.1.3), Bcl-2 (TC# 1.A.21.1.10), Beclin-1 (BECN1 or GT197; Q144570; TC# 9.A.15.2.1), and VPS34 (phosphatidylinositol 3-kinase, PI 3-kinase, PIK3C3), and coordinately prevents vascular autophagy and remodeling (Lv et al. 2020). A small molecule inhibitor of TMEM16A (2-bromodifluoroacetylamino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbox ylic acid o-tolylamide) blocks vascular smooth muscle contraction and lowers blood pressure in spontaneously hypertensive rats (Cil et al. 2021). Evodiamine and rutecarpine are TMEM16A inhibitors (Zhao et al. 2021). Cepharanthine is a selective ANO1 inhibitor with potential for lung adenocarcinoma therapy (Zhang et al. 2021). Benzophenanthridine alkaloids suppress lung adenocarcinoma by blocking TMEM16A Ca²⁺-activated Cl^- channels (Zhang et al. 2020). The diverse roles of TMEM16A Ca²⁺-activated Cl^- channels in inflammation have been described (Bai et al. 2021). TMEM16A-mediated breast cancer metastasis has been described in which ROCK1 increases TMEM16A channel activity via moesin phosphorylation.  An increase in TMEM16A channel activity promotes cell migration and invasion (Luo et al. 2021). Four Ca²⁺ sensing sites in TMEM16A have been identfied, and the activation properties of TMEM16A by them has been discussed (Ji et al. 2021). Blockade of TMEM16A protects against renal fibrosis by reducing the intracellular Cl^- concentration (Li et al. 2021). The TMEM16A/anoctamin 1 inhibitor T16Ainh-A01 reverses monocrotaline-induced rat pulmonary arterial hypertension (Xie et al. 2020). The role of TMEM16A/ERK/NK-1 signaling in dorsal root ganglia neurons in the development of neuropathic pain induced by spared nerve injury has been studied (Chen et al. 2021). Elevated ANO1 (DOG1) expression is frequent in colorectal cancer and is linked to molecular alterations (Jansen et al. 2022). ANO1 plays a role in the occurrence, development, metastasis, proliferation, and apoptosis of various malignant tumors. Guo et al. 2022 reviewed the mechanism of ANO1 involved in the replication, proliferation, invasion and apoptosis of various malignant tumors. Procyanidin (PC) is an efficacious and selective inhibitor of TMEM16A with an IC50 of 10.6 +/- 0.6 muM. The precise sites (D383, R535, and E624) of electrostatic interactions between PC and TMEM16A are known (Li et al. 2022). TMEM16A is a Ca²⁺activated Cl^- channel that plays critical roles in regulating vascular tone, sensory signal transduction, and mucosal secretion. TMEM16A activation also requires the membrane lipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) (Tembo et al. 2022). TMEM16A may promote angiogenesis of the heart during pressure-overload (Zhang et al. 2022), and it is an immunohistochemical marker of acinic cell carcinoma (Fiorentino et al. 2022). The progress in understanding solute carrier SLC families in nonalcoholic fatty liver disease has been reviewed (Tang et al. 2022). Arctigenin attenuates vascular inflammation induced by high salt through the TMEM16A/ESM1/VCAM-1 pathway (Zeng et al. 2022). Biologics that inactivate Na_v1.7 channels have the potential to reduce arthritis pain over a protracted period of time (Reid et al. 2022). Allicin, containing thiosulfinate moieties, inhibits TMEM16A) ion channel activity (Bai et al. 2023). TMEM16A) plays a role in pulmonary hypertension (Yuan et al. 2023). Chloride channels in biliary epithelial cells provide the driving force for biliary secretion. Norursodeoxycholic acid (norUDCA) potently stimulated chloride currents in mouse large cholangiocytes, which was blocked by siRNA silencing and pharmacological inhibition of TMEM16A (Truong et al. 2023).

Animals

Anoctamin 1a of Homo sapiens (Q5XXA6)

Anoctamin, Anoh-2.  Present in mechanoreceptive neurons and spermatheca (Wang et al. 2013).

Animals

Anoh-2 of Caenorhabditis elegans

Ca-ClC Family homologue

Ciliates

Ca-ClC homologue of Paramecium tetraurelia (A0CAP8)

Ciliate CaClC homologue

Alveolata

CaClC homologue of Paramecium tetraurelia (A0CIB0)

Water mold Anoctamin-like protein

Animal

Anoctamin-like protein of Phytophthora infestans (D0NGF4)

Uncharacterized protein

Fungi

Uncharacterized protein of Schizosaccharomyces japonicus

Anoctamin-like protein

Alveolata

Anoctamin-like protein of Oxytricha trifallax

TMEM16 (Ist2) ion channel/phospholipid scramblase of 735 aas and 8 - 10 TMSs (Malvezzi et al. 2013).  Three high-resolution cryo-EM structures of this scramblase, reconstituted in lipid nanodiscs, revealed that Ca²⁺-dependent activation of the scramblase entails global rearrangement of the transmembrane and cytosolic domains. Activation of the protein thins the membrane near the transport pathway to facilitate rapid transbilayer lipid movement (Falzone et al. 2019).

Fungi

Ist2 of Aspergillus fumigatus (Neosartorya fumigata)

TMEM16 of 735 aas and 10 TMSs.  Operates as a Ca²⁺-activated lipid scramblase (Wang et al. 2018). Each subunit of the homodimer contains a hydrophilic membrane-traversing cavity that is exposed to the lipid bilayer as a potential site of catalysis. This cavity harbours a conserved Ca²⁺-binding site, located within the hydrophobic core of the membrane. Mutations of residues involved in Ca²⁺ coordination affect both lipid scrambling in N. haematococca TMEM16 and ion conduction in the Cl^- channel of TMEM16A. The structure reveals the general architecture of the family and its mode of Ca²⁺ activation (Brunner et al. 2014). While the cytoplasmic portion of the protein is important for function, it does not appear to regulate scramblase activity via a detectable conformational change (Andra et al. 2018). Dynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca²⁺-bound nhTMEM16 (Khelashvili et al. 2019) (see family description). Permeation of potassium ions through the lipid scrambling path of nhTMEM16 has been documented (Cheng et al. 2022).

Fungi

TMEM16 of Nectria haematococca (Fusarium solani subsp. pisi)

Increased sodium tolerance protein, Ist2, of 946 aas and 7 TMSs.  Ist2 is an endoplasmic reticulum (ER)-resident transmembrane protein that mediates associations between the plasma membrane (PM) and the cortical ER (cER) in baker's yeast (Kralt et al. 2015).

Ist2 of Saccharomyces cerevisiae

Anoctamin 1, isoform b (Gnathodiaphyseal dysplasia 1 protein homologue) (39% identical to Anoctamin 1a) (Planells-Cases and Jentsch, 2009).  See also Xu et al. 2015.

Metazoa

Anoctamin 1b of Homo sapiens (Q75UR0)

Anoctamin 3, ANO3 or TMEM16C or KCNT1/Slack, of 981 aas and 9 putative TMSs.  Has calcium-dependent phospholipid scramblase activity, scrambling phosphatidylcholine and galactosylceramide. Seems to act as a potassium channel regulator and may inhibit pain signaling; can facilitate KCNT1/Slack channel activity by promoting its full single-channel conductance at very low sodium concentrations and by increasing its sodium sensitivity (Scudieri et al. 2012). Mutations cause  (i) epilepsy of infancy with migrating focal seizures (EIMFS; also known as migrating partial seizures in infancy), (ii) autosomal dominant nocturnal frontal lobe epilepsy, and (iii) other types of early onset epileptic encephalopathies (EOEEs) (Ohba et al. 2015). TMEM16C/Slack regulation of excitatory synaptic plasticity via GluA1-containing AMPA Receptors is critical for the pathogenesis of remifentanil-induced postoperative hyperalgesia in rats (Li et al. 2021). Specific mutational variants in TMS of ANO3 can be responsible for childhood-onset movement disorders with intellectual disability (Aihara et al. 2022).

ANO3 or KCNT1 of Homo sapiens

Ano5 (GDD1, TMEM16E), of 913 aas and 10 TMSs, is an intracellular calcium-activated chloride channel in the endoplasmic reticulum. It positively modulates bone homeostasis via calcium signaling in GDD (Li et al. 2022), and is associated with bone fragility, limb girdle muscular dystrophy type 2L (LGMD2L), Miyoshi myopathy type 3 (MMD3), and gnathodiaphyseal dysplasia 1 (GDD1) in humans (Jin et al. 2017), but an Ano5 knock-out mutant in mice was not reported to exhibit such symptoms (Xu et al. 2015). The orthologue in mice is TC# 1.A.17.1.2.  TMEM16E may function as a phospholipid scramblase in intracellular membranes, promoting sperm motility and function (Gyobu et al. 2016).  Dysregulated calcium homeostasis prevents plasma membrane repair in Anoctamin 5/TMEM16E-deficient patient muscle cells (Chandra et al. 2019). Ano5 is involved in familial florid osseous dysplasia (Lv et al. 2019). Pharmacological inhibition of ANO5 or lack of ANO5, prevent Ca²⁺ uptake into the ER following plasma membrane damage and Ca²⁺ overload (Chandra et al. 2021). Thus, Cl^- uptake into the ER is required to sequester injury-promoted cytosolic Ca²⁺. Anoctamin 5 regulates the cell cycle and affects the prognosis in gastric cancer (Fukami et al. 2022). Thus, ANO5 may be a key mediator in tumor progression and promises to be a prognostic biomarker for gastric cancer. TMEM16E regulates endothelial cell procoagulant activity and thrombosis (Schmaier et al. 2023).

Ano5 of Homo sapiens

Subdued, a calcium-activated chloride channel of 1075 aas. Functions in conjunction with the thermo-TRPs in thermal nociception. Subdued channels may amplify the nociceptive neuronal firing that is initiated by thermo-TRP channels in response to thermal stimuli (Jang et al. 2015). It may also act on phospholipids to transport or hydrolyze them (Le et al. 2019).

Subdued of Drosophila melanogaster

ANO-like protein of 921 aas and 9 predicted TMSs.

ANO-L family protein of Strongylocentrotus purpuratus (Purple sea urchin)

Duplicated full length anoctamin of 2084 aas and an etimated 20 TMSs.  The protein has two full length repeats, each of about 1000 aas with a ~500 aas hydrophilic domain followed by the first anoctamin domain, and then another 500 aa hydrophilic domain followed by the second anoctamin domain.

Dupicated anoctamin of Aphanomyces invadans

TMem16A or Anoctamin-1 (Ano1) Ca²⁺-activated anion (Cl^-) channel of 960 aas and 10 TMSs.  Its structure has been solved by cryoEM (Paulino et al. 2017). The protein shows a similar organization to the fungal nhTMEM16, except for changes at the site of catalysis. There, the conformation of transmembrane helices, constituting a membrane-spanning furrow that provides a path for lipids in scramblases, is replaced to form an enclosed aqueous pore that is largely shielded from the membrane (Paulino et al. 2017). It thus provides a pathway for anions such as Cl^-.  During activation, the binding of Ca²⁺ to a site located within the transmembrane domain, in the vicinity of the pore, alters the electrostatic properties of the ion conduction path and triggers a conformational rearrangement of an α-helix that comes into physical contact with the bound ligand, and thereby directly couples ligand binding and pore opening (Paulino et al. 2017).  The E143A mutant showed reduced sensitivity to Ca²⁺ but not to high temperatures, whereas the E705V mutant exhibited reduced sensitivity to both Ca²⁺ and noxious heat (Choi et al. 2018). Loss of TMEM16A resulted in reduced nephron number and, subsequently, albuminuria and tubular damage (Schenk et al. 2018). mAno1 expression is regulated via alternative promoters, and its transcriptional variation results in variation of the N-terminal sequence of the Ano1 protein due to alternative translation initiation sites (Kamikawa et al. 2018). The Ca²⁺ gating mechanism of TMEM16A, involving a Ca²⁺-sensing element close to the anion pore, alters conduction and substrate selection. De Jesús-Pérez et al. 2022 studied the gating-permeant anion relationship using mouse TMEM16A, showing that the apparent Ca²⁺ sensitivity increases with highly permeant anions and SCN^- mole fractions, likely by stabilizing bound Ca²⁺. Conversely, mutations in crucial gating elements, including the Ca²⁺-binding site 1,TMS 6, and the hydrophobic gate, impaired anion permeability and selectivity. Thus, there is a reciprocal rationship between gating and selectivity (De Jesús-Pérez et al. 2022).  Propagation of pacemaker activity and peristaltic contractions in the mouse renal pelvis rely on Ca²⁺-activated Cl^- Channels such as Ano1 and T-type Ca²⁺ channels (Grainger et al. 2022).

Ano1 of Mus musculus

Anoctamin-10 or TMEM16K of 660 aas and 9 or 10 TMSs.  In the presence of Ca²⁺, TMEM16K directly binds Ca²⁺ to form a stable complex (Ishihara et al. 2016). In the absence of Ca²⁺, TMEM16K and TMEM16F (TC# 1.A.17.1.4) aggregate, suggesting that their structures are stabilized by Ca²⁺.  Mutagenesis of acidic residues in TMEM16K's cytoplasmic and transmembrane regions identified five residues that are critical for binding Ca²⁺. These residues are well conserved between TMEM16F and 16K, and point mutations of these residues in TMEM16F reduced its ability to support Ca²⁺-dependent phospholipid scrambling (Ishihara et al. 2016). Phosphatidyl serine in the ER of mammalian cells is predominantly localized to the cytoplasmic leaflet, but TMEM16K directly or indirectly mediates Ca²⁺-dependent phospholipid scrambling (Tsuji et al. 2019). Ano10 plays roles in cell division, migration, apoptosis, cell signalling, and developmental processes (Chrysanthou et al. 2022).

TMEM16K of Homo sapiens

Anoctamin 7, ANO7, or TMEM16G, of 933 aas and 10 TMSs.  It has calcium-dependent phospholipid scramblase activity, scrambling phosphatidylserine, phosphatidylcholine and galactosylceramide, but it does not exhibit calcium-activated chloride channel (CaCC) activity. It may play a role in cell-cell interactions (Das et al. 2008). ANO7 is associated with aggressive prostate cancer (Kaikkonen et al. 2018). Insights into the topology and function of Ano7 have been described (Guo et al. 2021). Activation of calcium-activated chloride channels suppresses inherited seizure susceptibility in genetically epilepsy-prone rats (Thomas et al. 2022).

ANO7 of Homo sapiens

Anoctamin1, Ano1, TMEM16A of 979 aas and 10 TMSs. It is probably an anion (Cl^-) cannel. Fertilization activates TMEM16A channels in X. laevis eggs and induces the earliest known event triggered by fertilization: the fast block to polyspermy (Wozniak et al. 2018).

Ano1 of Xenopus laivis

Anoctamin-4, ANO4, TMEM16D, of 955 aas and 10 putative TMSs.  68% identical to ANO4 (TC# 1.A.17.1.20).  It has calcium-dependent phospholipid scramblase activity, scrambling phosphatidylserine, phosphatidylcholine and galactosylceramide, and it is a Ca²⁺-dependent non-selective cation channel (Reichhart et al. 2019). ANO4 is primarily expressed in the CNS and certain endocrine glands, and mutations affecting protein stability have been associated with various neuronal disorders (Reichhart et al. 2021).

.

ANO4 of Homo sapiens

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).  TMEM16A and TMEM16B are differentially expressed during development in the olfactory epithelium of the mouse (Maurya and Menini 2014).

Animals

TMEM16B of Homo sapiens (Q9NQ90)

Anoctamin-8, Ano8 or TMEM16H, of 1232 aas and 9 TMSs. It tethers the endoplasmic reticulum and plasma membrane for assembly of Ca²⁺ signaling complexes at the ER/PM compartment (Jha et al. 2019). ANO8 is a key tether in the formation of the ER/PM junctions that are essential for STIM1-STIM1 interaction and STIM1-Orai1 interaction and channel activation at a ER/PM PI(4,5)P₂-rich compartment. Moreover, ANO8 assembles all core Ca²⁺ signaling proteins: Orai1, PMCA, STIM1, IP₃ receptors, and SERCA2 at the ER/PM junctions to mediate a novel form of Orai1 channel inactivation by markedly facilitating SERCA2-mediated Ca²⁺ influx into the ER. This controls the efficiency of receptor-stimulated Ca²⁺ signaling, Ca²⁺ oscillations, and the duration of Orai1 activity to prevent Ca²⁺ toxicity (Jha et al. 2019).

Ano8 of Homo sapiens

Anoctamin 8, Ano8, of 1232 aas and ~ 8 or 9 TMSs. It may not exhibit calcium-activated chloride channel (CaCC) activity, but paclitaxel induces pyroptosis by inhibiting the volume‑sensitive chloride channel leucine‑rich repeat‑containing 8a in ovarian cancer cells (Yang et al. 2023).

.

Ano8 of Homo sapiens

Anoctamin-6 (ANO6: TMEM16F) Ca²⁺-dependent phospholipid scramblase (flippase) (Suzuki et al., 2010; Chauhan et al. 2016). Defects cause Scott syndrome, and promote assembly of the tenase and prothrombinase complexes involved in blood coagulation (Fujii et al. 2015). 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 (see also Segawa et al. 2011).  TMEM16C, 16D, 16G and 16J also have Ca²⁺-dependent scramblase activities but not channel activity (Suzuki et al. 2013).  The pore region suggested to be resonsible for Cl^- transport in TMEM16A is also responsible for phospholipid scramblase activity (Suzuki et al. 2014).  Anoctamin-6 (Ano6) plays an essential role in C2C12 myoblast proliferation, probably by regulating the ERK/AKT signaling pathway (Zhao et al. 2014).  It regulates baeline phosphatidyl serine exposure and cell viability in human embryonic kidney cells (Schenk et al. 2016). A single TMEM16F molecule transports phospholipids nonspecifically between the membrane bilayers dependent on Ca²⁺. Thermodynamic analyses indicated that TMEM16F transports 4.5 x 10⁴ lipids per second at 25 degrees C, with an activation free energy of 47 kJ/mol, suggesting a channel-dependent, facilitated diffusion,"stepping-stone" mechanism (Watanabe et al. 2018). TMEM16F plays roles in platelet activation during blood clotting, bone formation, and T cell activation. Activation of TMEM16F by Ca²⁺ ionophores triggers large-scale surface membrane expansion in parallel with phospholipid scrambling (Bricogne et al. 2019). With continued ionophore application,TMEM16F-expressing cells undergo extensive shedding of ectosomes which incorporate The T cell co-receptor PD-1. Cells lacking TMEM16F fail to expand the surface membrane in response to elevated cytoplasmic Ca²⁺and instead undergo endocytosis with PD-1 internalization. This suggests a new role for TMEM16F as a regulator of Ca²⁺-activated membrane trafficking (Bricogne et al. 2a019). The inner activation gate consists of  three hydrophobic residues, F₅₁₈, Y₅₆₃ and I₆₁₂, in the middle of the phospholipid permeation pathway. Disrupting the inner gate profoundly alters phospholipid permeation. Lysine substitutions of F518 and Y563 lead to constitutively active CaPLSases that bypass Ca²⁺-dependent activation. An analogous lysine mutation to TMEM16F-F518 in TMEM16A (L543K) is sufficient to confer CaPLSase activity to the Ca²⁺-activated Cl^- channel (CaCC) (Le et al. 2019).  ANO6, by virtue of its scramblase activity, may play a role as a regulator of the ADAM-network in the plasma membrane. TMEM16F inhibition limits pain-associated behavior and improves motor function by promoting microglia M2 polarization in mice (Zhao and Gao 2019). Polyphenols do not inhibit the phospholipid scramblase activity of TMEM16F (Le et al. 2020). TMEM16F is a ubiquitously expressed Ca²⁺-activated phospholipid scramblase that also functions as a largely non-selective ion channel with open, closed and intermediate conformations (Jia et al. 2022). An inner activation gate consists of F518, Y563, and I612, and  charged mutations of the inner gate residues leads to constitutively active mammalian (m)TMEM16F scrambling. Lysine substitution of F518 and Y563 leads to spontaneous opening of the permeation pore in the Ca²⁺-bound state of mTMEM16F. Dilation of the pore exposes hydrophilic patches in the upper pore region, greatly increases the pore hydration level, and enables lipid scrambling (Jia et al. 2022).

Animals

Anoctamin-6 of Homo sapiens (Q4KMQ2)

Anoctamin-9 (Transmembrane protein 16J) (Tumor protein p53-inducible protein 5) (p53-induced gene 5 protein).  It promotes pancreatic tumorigenesis (Jun et al. 2017).

Animals

ANO9 of Homo sapiens

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

Anoctamin, Anoh-1 of 822 aas.  Functions in a sensory mode-specific manner.  Present inamphid sensory neurons to detect external chemical and nociceptive cues (Wang et al. 2013).

Animals

Anoh-1 of Caenorhabditis elegans

DUF590 family protein

Slime molds

DUF590 protein of Dicyostelium discoideum (Q54BH1)

TMEM16 homologue of 701 aas.

Heterolobosea

TMEM16 homologue of Naegleria gruberi (Amoeba)

Anoctamin homologue of 689 aas

Cryptophyta

Anoctamin of Guillardia theta

DUF590 homologue of 487 aas

Amoebozoa

DUF590 homologue of Entamoeba nuttalli

DUF590 protein of 914 aas

DUF590 protein of Allomyces macrogynus

Uncharacterized protein of 569 aas and 8 predicted TMSs.

UP of Dictyostelium fasciculatum (Slime mold)

Uncharacterized protein of 2464 aas and 11 TMSs.  Contains a trypsin-like serine protease domain (residues 100 - 400), a rabaptin (chromosome segregation) domain (residues 900 - 1200), an anoctamin domain (residues 1500 - 2000) and an AAA ATPase-containing von Willebrand factor type A domain (residues 2200 - 2500).

Stramenopiles

UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana)

Uncharacterized protein of 1080 aas

Plants

UP of Ostreococcus lucimarinus

Anoctamin homologue of 1265 aas

Alveolata (ciiates)

Anoctamin homologue of Tetrahymena thermophila

Uncharacterized protein of 995 aas and 8 TMSs.

UP of Tetrahymena thermophila

Uncharacterized protein of 10 TMSs in a 3 + 4 +3 arrangement

UP of Paramecium tetraurelia

Uncharacterized protein of 888 aas and 10 TMSs in a 3 + 4 + 3 arrangement

UP of Paramecium tetraurelia

Uncharacterized protein of 958 aas and 11 or 12 TMSs in a 3 or 4 + 5 +3 arrangement.

UP of Paramecium tetraurelia

Uncharacterized protein of 842 aas and 9 TMSs.

Stramenopiles

UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana)

Uncharacterized protein of 835 aas and 9 TMSs.

Stramenopiles

UP of Phytophthora parasitica (Potato buckeye rot agent)

Uncharacterized protein of 1231 aas and 9 TMSs

Stramenopiles

UP of Aureococcus anophagefferens (Harmful bloom alga)

Uncharacterized protein of 945 aas and 8 TMSs

Stramenopiles

UP of Ectocarpus siliculosus (Brown alga)

Uncharacterized protein of 1437 aas

Haptophyceae

UP of Emiliania huxleyi

Uncharacterized protein of 1150 aas

Ichthyosporea

UP of Capsaspora owczarzaki

DUF590/putative methyltransferase of 1221 aas and 10 TMSs.

Alveolata

DUF490 homologue of Oxytricha trifallax

DUF590 homologue of 1026 aas and 10 TMSs

Alveolata

DUF590 homologue of Paramecium tetraurelia (ciliate)

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).  TMC1 and TMC2 are both components of hair cell transduction channels and contribute to permeation properties (Pan et al. 2013; Kawashima et al. 2014).  Both TMC1 and 2 interact with Protocadherin 15 (Maeda et al. 2014). TMC1 and TMC2 are components of the stereocilia mechanoelectrical transduction channel complex (Kurima et al. 2015). While TMC2 is required for mechanotransduction in mature vestibular hair cells, its expression in the immature cochlea may be an evolutionary remnant (Corns et al. 2017). Transgenic Tmc2 expression preserves inner ear hair cells and vestibular function in mice lacking Tmc1 (Asai et al. 2018). Gentamicin and other antibiotics enters neonatal mouse hair cells predominantly through sensorymMechanoelectrical transduction channels, Tmc1 and Tmc2 (Makabe et al. 2020).

Animals

TMC2 of Mus musculus (Q8R4P4)

Transmembrane channel 6, TMC6/EVER1 of 805 aas.  Mutations give rise to epidermodysplasia verruciformis (EV), a rare genodermatosis, characterized by increased sensitivity to infection by the beta-subtype of human papillomaviruses (beta-HPVs), causing persistent, tinea versicolor-like dermal lesions (Horton and Stokes 2014). Biallelic mutations in either TMC6 or TMC8 are detected in more than half of the cases of the pre-malignant skin disease epidermodysplasia verruciformis (EV) which together form a complex with CIB1 (TC# 8.A.82.1.9) (Wu et al. 2020).

Animal

TMC6 of Homo sapiens

Transmembrane channel 8, TMC8/EVER2/EVIN2 of 726 aas.  Mutations give rise to epidermodysplasia verruciformis (EV), a rare genodermatosis characterized by increased sensitivity to infection by the beta-subtype of human papillomaviruses (beta-HPVs) as well as increased incidence of cancer, causing persistent, tinea versicolor-like dermal lesions (Horton and Stokes 2014).  This is due to release of Zn²⁺ and Ca²⁺ from the endoplasmic reticulum (Sirianant et al. 2014).  The channel-like domain has been identified (Miyauchi et al. 2016). It plays a role in several aspects of human pathophysiology, such as ion channel permeability, human papillomavirus infection and skin cancer (Lu et al. 2017). Biallelic mutations in either TMC6 or TMC8 are detected in more than half of the cases of the pre-malignant skin disease epidermodysplasia verruciformis (EV), which together form a complex with CIB1 (TC# 8.A.82.1.9) in lymphocytes (Wu et al. 2020). TMC8 is a prognostic immune-associated gene in head and neck squamous cancer (HNSC) cells (Lin et al. 2021).

Animals

TMC8 of Homo sapiens

Transmembrane channel protein 3, Tmc3 of 1130 aas (Kurima et al. 2003; Beurg et al. 2014). LPS-inducible lncRNA TMC3-antisense-1 (AS1) negatively regulates the expression of IL-10 (Ye et al. 2020). In the brown planthopper, Nilaparvata lugens, TMCs is highly expressed in the female reproductive organ especially in the oviduct (Jia et al. 2020). RNAi-mediated silencing of Nltmc3 substantially decreased the egg-laying number and impaired ovary development.

Animals

Tmc3 of Mus musculus

Tmc1/Tmc2a or Tmc2b/protocadherin 15a (Pcdh15a). The complex is part of a mechanotransduction system (Maeda et al. 2014). Its trafficing to the plasma membrane depends on the transmembrane O-methyltransferase (TOMT/LRTOMT; 259 aas, 1 N-terminal TMS) (Erickson et al. 2017). Water motion is dependent on this complex (Chou et al. 2017). The role of another protein, Tmie (see TC# 8.A.115), in sensory hair cells is to target and stabilize the Tmc channel subunits to the stereocilia, the site of mechano-electrical transduction (Pacentine and Nicolson 2019). Tmc proteins 1, 2a and 2b are essential for zebrafish hearing although Tmc1 is not, probably because they can (at least partially) substitute for each other (Chen et al. 2020). There are two distinct cell types in inner ear hairs, an upper layer of teardrop shaped cells that rely on Tmc2a, and a lower layer of gourd shaped cells that rely on Tmc1/2b (Smith et al. 2020). Tmc reliance in the ear is dependent on the organ, subtype of hair cell, position within the ear, and axis of best sensitivity (Zhu et al. 2020).

Animals

Tmc1/Tmc2/Pcdh15 complex of Danio rerio (Zebrafish) (Brachydanio rerio)

Tmc4 (MBOAT7) of 712 aas and 10 TMSs (Mancina et al. 2016). It is a calcium-dependent chloride channel that may play a role in nonalcoholic fatty liver disease (NAFLD) (Sookoian et al. 2018) but is not associated with a risk of hepatocellular carcinoma or persistent hepatitis B infection (Wang et al. 2021). Ibuprofen only minimally inhibits the taste response of the ENaC to NaCl, but it significantly inhibits the TMC4 response to NaCl with an IC50 at 1.45 mM. Thus, ibuprofen interferes with detection of salty taste via inhibition of TMC4 (Kasahara et al. 2021). This agrees with the fact that TMC4 is a chloride channel involved in high-concentration salt taste sensation (Kasahara et al. 2021). TMC4 is involved in pH and temperature-dependent modulation of salty taste (Kasahara et al. 2021). Salt-enhancing peptides were identified based on the allosteric sites in TMC4 (Shen et al. 2022). Mechanisms of salt taste reception and the properties of TMC4 as a  salt taste-related molecule have been reviewed (Kasahara et al. 2022). Genetic polymorphisms in TMC4 predispose organisms to a higher risk of liver diseases (Rivera-Iñiguez et al. 2022). Umami peptides bind to the TMC4 receptor to enhance saltiness (Xie et al. 2023).

TMC4 of Homo sapiens

The mechanoelectric-transduction (MT or MET) complex in auditory hair cells converts the mechanical stimulation of sound waves into neural signals. Tmc1 is of 760 aas and 10 TMSs and is 96% identical to mouse TMC1 (TC# 1.A.17.4.6). Novel TMC1 structural and splice variants are associated with congenital nonsyndromic deafness (Meyer et al. 2005). Variants responsible for hereditary hearing loss have been identified (Wang et al. 2018). There are varying numbers of channels per MET complex, each requiring multiple TMC1 molecules, and together operating in a coordinated, cooperative manner (Beurg et al. 2018). Ballesteros et al. 2018 generated a model of TMC1 based on X-ray and cryo-EM structures of TMEM16 proteins, revealing the presence of a large cavity near the protein-lipid interface that harbors the Beethoven mutation, suggesting that it functions as a permeation pathway. Hair cells are permeable to 3 kDa dextrans, and dextran permeation requires TMC1/2 proteins and functional MET channels (Ballesteros et al. 2018). TMC1 is a pore-forming component of MET channels in auditory and vestibular hair cells (Pan et al. 2018). KCNQ1 rescues TMC1 plasma membrane expression but not mechanosensitive channel activity (Harkcom et al. 2019). A Tmc1 mutation reduces calcium permeability and expression of MET channels in cochlear hair cells (Beurg et al. 2019). Deafness mutation D572N of TMC1 destabilizes TMC1 expression by disrupting LHFPL5 binding (Yu et al. 2020). Homozygous variants in the TMC1 and CDH23 (3354 aas and at least two TMSs, one N-terminal and one near the C-terminus; Q9H251) genes cause autosomal recessive nonsyndromic hearing loss (Zardadi et al. 2020). TMC1 forms a complex with protocadherin 15 (PCDH15, TC# 1.A.82.1.1), lipoma HMGIC fusion partner-like 5 (LHFPL5, TC# 1.A.82.1.1), and transmembrane inner ear protein (TMIE, TC# 8.A.116.1.2). Splicing isoforms of TMC1, LHFPL5, and TMIE have been identified (Zhou et al. 2021). There are four alternative splicing events for the genes encoding these three proteins. The alternative splicing of TMC1 and LHFPL5 is cochlear-specific and occurs in both neonatal and adult (mouse) cochleae (Zhou et al. 2021). Tmc1 deafness mutations impact mechanotransduction in auditory hair cells (Beurg et al. 2021). A TMC1 synonymous substitution is a variant disrupting splicing regulatory elements associated with recessive hearing loss (Vaché et al. 2021). The roles of solute carriers in auditory function have been reviewed (Qian et al. 2022). Autosomal recessive and dominant non-syndromic hearing loss can be due to pathogenic TMC1 variants (Kraatari-Tiri et al. 2022). Mechanical gating of the auditory transduction channel TMC1 involves the fourth and sixth TMSs (Akyuz et al. 2022). Regulation of membrane homeostasis by TMC1 mechanoelectrical transduction channels is essential for hearing (Ballesteros and Swartz 2022). The conductance and organization of the TMC1-containing mechanotransducer channel complex in auditory hair cells has been examined, and it was concluded that each PCDH15 (see 1.A.17.4.13 and 1.A.82.1.1) and LHFPL5 (see 1.A.17.4.15 and 1.A.82.1.1) monomer may contact two channels, irrespective of location (Fettiplace et al. 2022).

.

TMC1 of Homo sapiens

TMC5, of 1006 aas and 11 putative TMSs, promotes prostate cancer cell proliferation through cell cycle regulation and could be a target for treatment (Zhang et al. 2019).

TMC5 of Homo sapiens

Transmembrane channel-like protein 1 of 878 aas and ~ 11 TMSs (Erives and Fritzsch 2019). Mechanosensory transduction (MT) in specialized hair cells of the inner ear may be mediated by TMC1 as the pore component. Other components of the MT complex include protocadherin 15, cadherin 23, lipoma HMGIC fusion partner-like 5, transmembrane inner ear, calcium and integrin-binding family member 2, and ankyrins (Zheng and Holt 2020).

TMC1 of Amphimedon queenslandica

Transmembrane channel-like (TMC7) protein, of 723 aas and 11 TMSs. It probably transports  Ca²⁺, and other cations. It is important for oral tongue squamous cell carcinoma (OTSCC), with rapid local invasion and metastasis. The  long noncoding (lnc) RNA MIR4713HG is markedly upregulated in OTSCC. Upregulation of MIR4713HG promotes cell proliferation and metastasis (Jia et al. 2021). Micro RNA let7c5p physically binds MIR4713HG, and knockdown of let7c5p counteracts the effect of MIR4713HG on OTSCC. let7c5p exerted this role by affecting the expression level of TMC7 (Jia et al. 2021). TMC7 also affects other types (rectal and panrecatic) of cancer (Watanabe et al. 2014; Cheng et al. 2019), and may be associated with psychosis proneness (Ortega-Alonso et al. 2017).

TMC7 of Homo sapiens

Transmembrane channel-like protein-B, Tmc8 (EVER2).  It occurs in the endoplasmic reticulum where it functions to release Ca²⁺ and Zn²⁺ and supresses Cl^- currents (Sirianant et al. 2014). The functional variant, rs7208422 of the TMC8 gene, has been suggested to have a high impact on susceptibility to beta-papillomaviruses and their oncogenic potential and to also have an influence on alpha-type HPV-related disease (Stoehr et al. 2021).

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 cochlear-expressed protein-1, Beethoven protein and deafness protein.  Required for normal function of cochlear hair cells, possibly as a Na⁺/K⁺/Ca²⁺ channel (Kim and Fettiplace 2013).  TMC1 and TMC2 are both components of hair cell transduction channels and contribute to permeation properties (Pan et al. 2013; Kawashima et al. 2014).  Channel activity has been demonstrated for the C. elegans orthologue, and the mouse Tmc1.  The C. elegans Tmc1 is probably a Na⁺-activated Na⁺-selective mechanosensor. The C. elegans Tmc2 may be a Na⁺/K⁺ channel.  The mouse Tmc1 is functional and replaces Tmc2 when expressed in C. elegans (WR Schafer, personal communication).  Ca²⁺ currents are blocked by the peptide toxin GsMTx-4 (Beurg et al. 2014).  Tmc1 and Tmc2, expressed in cochlear and vestibular hair cells, are required for hair cell mechanoelectric transduction (Nakanishi et al. 2014); mutations disrupt mechanoelectric transduction and are a cause of autosomal dominant and recessive forms of nonsyndromic hearing loss (Gao et al. 2015).  Using the mutant mouse model (Tmc1; Beethoven) for progressive hearing loss in humans (DFNA36) this mutation has been shown to affect the MET channel pore, reducing its Ca²⁺ permeability and its affinity for the permeant blocker, dihydrostreptomycin (Corns et al. 2016).  Evidence for TMC1 being the hair cell mechanosensitive channel has been evaluated (Fettiplace 2016).  The human orthologue (UniProt acc # Q8TDI8) is 96% identical. Mouse LHFPL5 ((HMGIC fusion partner-like protein 5) co-expresses with TMC1 in auditory hair cells (Li et al. 2019). A region within the N-terminus of mouse TMC1 (residues 138 - 168) precludes trafficking from an intracellular location to the plasma membrane (Soler et al. 2019). TMC1 is an essential component of a leak channel that modulates tonotopy and excitability of mouse auditory hair cells (Liu et al. 2019). VRISPER/Cas has been used to correct defects that result in hereditary hearing loss (Farooq et al. 2020). Repair of Tmc1 via genetic engineering in vivo restored inner hair cell sensory transduction and hair cell morphology and transiently rescued low-frequency hearing (Yeh et al. 2020).

Animals

Tmc1 of Mus musculus

The sodium sensor/cation conductance channel activated by high extracellular Na⁺, Tmc-1 (Tmc1) (Chatzigeorgiou et al. 2013).  It functions in salt taste chemosensation and salt avoidance and is an ionotropic sensory receptor.  Wang et al. 2016 showed that C. elegans TMC-1 mediates nociceptor responses to high pH, not sodium, allowing the nematode to avoid strongly alkaline environments in which most animals cannot survive (Spalthoff and Göpfert 2016).  TMC-1 and TMC-2 are required for normal egg laying in C. elegans. Mutations in these proteins cause membrane hyperpolarization and disrupt the rhythmic calcium activities in both neurons and muscles involved in egg laying. Mechanistically, TMC proteins enhance membrane depolarization through background leak currents, and ectopic expression of both C. elegans and mammalian TMC proteins results in membrane depolarization (Yue et al. 2018). TMC-1 is necessary for sodium attraction, but not aversion in the nematode. Dao et al. 2020 showed that TMC-1 contributes to the nematode's lithium induced attraction behavior, but not potassium or magnesium attraction, thus clarifying the specificity of the response. In addition, they found that sodium conditioned aversion is dependent on TMC-1 and disrupts both sodium- and lithium-induced attraction (Dao et al. 2020). The C. elegans Tmc-1 is involved in egg-laying inhibition in response to harsh touch (Kaulich et al. 2021). The initial step in the sensory transduction pathway underpinning hearing and balance in mammals involves the conversion of force into the gating of a mechanosensory transduction channel. Jeong et al. 2022 reported the single-particle cryo-EM structure of TMC-1 from C. elegans. The two-fold symmetric complex is composed of two copies each of the pore-forming TMC-1 subunit, the calcium-binding protein CALM-1 and the transmembrane inner ear protein TMIE. CALM-1 (see TC# 8.A.82.1.1) makes contacts with the cytoplasmic face of the TMC-1 subunits, whereas the single-pass TMIE subunits (see TC# 8.A.116) reside on the periphery of the complex, poised like the handles of an accordion. A subset of complexes  includes a single arrestin-like protein, arrestin domain protein (ARRD-6; see TC# 8.A.136.1.15), bound to a CALM-1 subunit. Single-particle reconstructions and molecular dynamics simulations showed how the mechanosensory transduction complex deforms the membrane bilayer to suggest roles for lipid-protein interactions in the mechanism by which mechanical force is transduced to ion channel gating (Jeong et al. 2022).

Animals

TMC-1 of Caenorhabditis elegans

Tmc2 channel of 1203 aas and 9 - 11 TMSs; functions in touch neurons as a mechanosensitive touch sensor (Chatzigeorgiou et al. 2013; WR Schafer, personal communication).  May function as a Na⁺/K⁺ channel.  TMC-1 and TMC-2 are required for normal egg laying in C. elegans. Mutations in these proteins cause membrane hyperpolarization and disrupt the rhythmic calcium activities in both neurons and muscles involved in egg laying. Mechanistically, TMC proteins enhance membrane depolarization through background leak currents, and ectopic expression of both C. elegans and mammalian TMC proteins results in membrane depolarization (Yue et al. 2018).

Animals

Tmc2 of Caenorhabditis elegans

Tmc receptor/channel of 1932 aas and about 10 TMSs. Plays a role in Drosophila proprioception and the sensory control of larval locomotion (Guo et al. 2016). These Tmc channels may be activated by membrane curvature in dendrites that are exposed to strain, possibly explaining how different cellular systems rely on a common molecular pathway for mechanosensory responses (He et al. 2019).

Animals (fruit flies)

Tmc of Drosophila melanogaster

Uncharacterized protein, DUF221, of 703 aas

Plants

UP of Zea mays

The non-rectifying, plasma membrane, calcium-permeable, stress-gated, cation channel 1 (CSC1) of 771 aas (Hou et al. 2014).  Activated by hyperosmotic shock.  Permeable to Ca²⁺, K⁺ and Na⁺.  Inactivation or closure is Ca²⁺-dependent.  The N-terminal region contains 3 TMSs, the first of which may be a cleavable signal peptide., and the C-terminal region contains 6 TMSs corresponding to the DUF221 domain.  Arabidopsis contains at least 15 CSCs ((Hou et al. 2014).  Some plant homologues are transcriptionally upregulated in response to vaious abiotic and biotic stresses involving mechanical perturbation (Kiyosue et al. 1994).

Plants

CSC1 of Arabidopsis thaliana

Osmotically-gated calcium conductance channel of 782 aas. CSC1 (Hou et al. 2014). Activated under hyperosmotic conditions. There are four paralogues in S. cerevisiae. 

Fungi

CSC1 of Saccharomyces cerevisiae

The osmosensitive calcium-permeable cation channel, CSC1 or Tmem63c, of 806 aas and ~10 TMSs.  It is activated by hyperosmolarity and Ca²⁺ (Hou et al. 2014). Tmem63c is a potential pro-survival factor in angiotensin II-treated human podocytes (Eisenreich et al. 2020). It is regulated by microRNA-564 and transforming growth factor beta (TGFβ) in human renal cells, and is therefore a potential target for albuminuria development (Orphal et al. 2020). TMEM63C mutations cause mitochondrial morphology defects and underlie hereditary spastic paraplegia (Tábara et al. 2022).

Animals

CSC1 of Homo sapiens

Uncharacterized protein of 901 aas

UP of Spironucleus salmonicida

Uncharacterized protein of 1267 aas and 12 TMSs

UP of Dictyostelium discoideum (Slime mold)

Uncharacterized protein of 1548 aas and 12 TMSs.

UP of Thalassiosira pseudonana (Marine diatom) (Cyclotella nana)

Uncharacterized protein of 1172 aas

UP of Phytomonas sp. isolate EM1

Uncharacterized protein of 1258 aas and 11 TMSs.

UP of Agaricus bisporus (White button mushroom)

Csc1 homologue of 866 aas and ~ 11 TMSs. Deletioin of this gene causes C. albicans to become senstive to cations and SDS, tolerant to antifungal agents and produce filamentation (Jiang and Yang 2018).

Csc1 homologue of Candida albicans

OSCA1.2 of 772 aas and 11 TMSs.  It is a dimer containing eleven TMSs per subunit, similar to other TMEM16 proteins. Jojoa Cruz et al. 2018 located the ion permeation pathway within each subunit by demonstrating that a conserved acidic residue is a determinant of channel conductance. Molecular dynamics simulations revealed membrane interactions, suggesting a role of lipids in gating.  The high resolution structure of this hyperosmolality-gated calcium-permeable channel has been determined (Liu et al. 2018). It contains 11 TMSs and forms a homodimer. The pore-lining residues were clearly identified. Its cytosolic domain contains an RNA recognition motif and two unique long helices. The linker between these two helices forms an anchor in the lipid bilayer and may be essential to osmosensing. Genome-wide analyses of OSCA gene family members in Vigna radiata have revealed their involvement in the osmotic response (Yin et al. 2021).

OSCA1.2 of Arabidopsis thaliana (Mouse-ear cress)

Uncharacterized protein of 816 aas containe a DUF221 domain

Animals

UP of Danio rerio

Dimeric OSCA1.2 of 766 aas and 11 TMSs.  The 3-D structure has been determined (K. Maity et al., PNAS, in press).  This protein is 69% identical to the A. thaliana ortholog (TC# 1.A.17.5.10). It is a putative early stress-responsive osmolality-sensing ion channel protein. A model has been proposed by which it may mediate hyperosmolality-sensing and consequent gating of ion transport. It has a cytosolic domain structurally related to RNA recognition proteins that includes helical arms paralell to the plane of the membrane.  They may sense lateral tension in the inner leaflet, caused by changes in turgor pressure, allowing gating of the channel via coupling of the two domains.

OSCA1.2 of Oryza sativa subsp. japonica (Rice)

TMEM63A or CSC1-like protein of 807 aas and ~10 TMSs. Heterozygous variants in TMEM63A have been identified as the cause of infantile-onset transient hypomyelination. TMEM63A variants are thought to cause transient hypomyelination with favorable developmental progress, but identification of a novel TMEM63A variant showed that the TMEM63A-related clinical spectrum is broad and includes severe developmental delay with seizures (Fukumura et al. 2021).

TMEM63A of Homo sapiens

Uncharacterized transmembrane protein 63B of 832 aas with a DUF221 domain.

Animals

UP of Homo sapiens

Uncharacterized transmembrane protein 63B of 832 aas with a DUF221 domain.

Amoebozoa

UP of Acanthamoeba castellanii

Uncharacterized protein of 853 aas with a DUF221 domain.

Fungi

UP of Botryotinia fuckeliana

Phosphate metabolism protein 7, Phm7

Yeast

Phm7 of Saccharomyces cerevisiae

Sporulation-specific protein 75, Spo75

Yeast

Spo75 of Saccharomyce cerevisiae

RSN-1-like protein of 957 aas

Yeast

RSN-1-like protein of Saccharomyces kudriavzevii

Early response to dehydrate stress protein, ERD4 of 785 aas. The orthologous channel protein in Dionaea muscipula may play a role in touch-induced hair calcium-electrical signals that excite the Venus flytrap (Scherzer et al. 2022).

Plants

ERD4 of Arabidopsis thaliana

Uncharacterized protein of 878 aas and 7 putative TMSs.

Alveolata

UP of Oxytricha trifallax

Uncharacterized protein of 707 aas and 10 TMSs

UP of Plasmodiophora brassicae

TMC-like protein 8 of 890 aas and 8 TMSs

Alveolata

TMC homologue of Oxytricha trifallax

Uncharacterized protein of 834 aas and 7 TMSs

Alveolata

UP of Oxytricha trifallax

Uncharacterized protein of 912 aas and 10 TMSs

Stramenopiles

UP of Phytophthora parasitica (Potato buckeye rot agent)

Uncharacterized protein of 620 aas and 9 TMSs

Stremenopiles

UP of Ectocarpus siliculosus (Brown alga)

Uncharacterized protein of 865 aas and 10 TMSs

Cryptophyta

UP of Guillardia theta

TMC protein of 890 aas and 10 TMSs

Alveolata

TMC protein of Tetrahymena thermophila

Uncharacterized protein of 1057 aas and 10 TMSs.

UP of Tetrahymena thermophila

Uncharacterized protein of 867 aas and 10 TMSs.

UP of Saprolegnia diclina

Uncharacterized protein of 836 aas and 12 TMSs.

UP of Giardia intestinalis (Giardia lamblia)

Uncharacterized protein of 637 aas and 8 TMSs.

UP of Spironucleus salmonicida

Distant Anoctamin homologue of 718 aas and 14 TMSs in a 4 + 1+1+1+2+2+2+1 arramgement.

Anoctamin homologue of Spironucleus salmonicida

Uncharacterized Anoctamin homologue of 502 aas and 8 putative TMSs

UP of Spironucleus salmonicida

Uncharacterized anoctamin homologue of 823 aas and 8 predicted TMSs in a 3 + 2 + 3 arrangement.

UP of Giardia intestinalis (Giardia lamblia)