TheCalcium-Dependent Chloride Channel (Ca-ClC) proteins (orcalcium-activated chloride channels (CaCCs),[2] are heterogeneous groups ofligand-gated ion channels forchloride that have been identified in manyepithelial andendothelial cell types as well as insmooth muscle cells. They include proteins from several structurally different families: chloride channel accessory (CLCA),[3] bestrophin (BEST),[4][5] and calcium-dependent chloride channel anoctamin (ANO or TMEM16) channels[4][5][6][7]ANO1 is highly expressed in human gastrointestinalinterstitial cells of Cajal, which are proteins which serve as intestinal pacemakers forperistalsis.[6] In addition to their role as chloride channels some CLCA proteins function as adhesion molecules and may also have roles astumoursuppressors.[8] These eukaryotic proteins are "required for normal electrolyte and fluid secretion, olfactory perception, and neuronal and smooth muscle excitability" in animals.[9][10] Members of the Ca-CIC family are generally 600 to 1000 amino acyl residues (aas) in length and exhibit 7 to 10 transmembrane segments (TMSs).
Tmc1 and Tmc2 (TC#s 1.A.17.4.6 and1.A.17.4.1, respectively) may play a role in hearing and are required for normal function of cochlear hair cells, possibly as Ca2+ channels or Ca2+ channel subunits (see also familyTC# 1.A.82).[11] Mice lacking both channels lack hair cell mechanosensory potentials.[12] There are 8 members of this family in humans, 1 inDrosophila and 2 inC. elegans. One of the latter two is expressed in mechanoreceptors.[13] Tmc1 is a sodium-sensitive cation channel required for salt (Na+) chemosensation inC. elegans "where it is required for salt-evoked neuronal activity and behavioural avoidance of high concentrations of NaCl".[14]
TMEM16A is over-expressed in several tumor types. The role of TMEM16A in gliomas and the potential underlying mechanisms were analyzed by Liu et al. 2014. Knockdown of TMEM16A suppressed cell proliferation, migration and invasion.[15]
The reactions believed to be catalyzed by channels of the Ca-ClC family are:[16]
^ The anoctamins are only expressed ineukaryotes, with 10 members invertebrates.[7] Although all anoctamins are calcium-activated, not all members of this family are ion channels like ANO1; some arephospholipid scramblases.[7] ANO1 was the first anoctamin discovered, with three research groups independently identifying it in 2008.[7] A single protein homologue to the vertebrate anoctamins has been found in fungi and yeast,Aspergillus fumigatus andSaccharomyces cerevisiae, respsectively.[7]
^Pang C, Yuan H, Ren S, Chen Y, An H, Zhan Y (1 January 2014). "TMEM16A/B associated CaCC: structural and functional insights".Protein and Peptide Letters.21 (1):94–9.doi:10.2174/09298665113206660098.PMID24151904.
Kunzelmann K, Cabrita I, Wanitchakool P, Ousingsawat J, Sirianant L, Benedetto R, Schreiber R (March 2016). "Modulating Ca²⁺ signals: a common theme for TMEM16, Ist2, and TMC".Pflügers Archiv.468 (3):475–90.doi:10.1007/s00424-015-1767-4.PMID26700940.S2CID14374080.
Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM, Raouf R, Shin YK, Oh U (October 2008). "TMEM16A confers receptor-activated calcium-dependent chloride conductance".Nature.455 (7217):1210–5.Bibcode:2008Natur.455.1210Y.doi:10.1038/nature07313.PMID18724360.S2CID205214858.
