The Calcium-Dependent Chloride Channel (Ca-ClC) proteins (or calcium-activated chloride channels (CaCCs), are heterogeneous groups of ligand-gated ion channels for chloride that have been identified in many epithelial and endothelial cell types as well as in smooth muscle cells. They include proteins from several structurally different families: chloride channel accessory (CLCA), bestrophin (BEST), and calcium-dependent chloride channel anoctamin (ANO or TMEM16) channels]]ANO1 is highly expressed in human gastrointestinal interstitial cells of Cajal, which are proteins which serve as intestinal pacemakers for peristalsis. In addition to their role as chloride channels some CLCA proteins function as adhesion molecules and may also have roles as tumoursuppressors. These eukaryotic proteins are "required for normal electrolyte and fluid secretion, olfactory perception, and neuronal and smooth muscle excitability" in animals. 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 and 1.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 family TC# 1.A.82). Mice lacking both channels lack hair cell mechanosensory potentials. There are 8 members of this family in humans, 1 in Drosophila and 2 in C. elegans. One of the latter two is expressed in mechanoreceptors. Tmc1 is a sodium-sensitive cation channel required for salt (Na+) chemosensation in C. elegans "where it is required for salt-evoked neuronal activity and behavioural avoidance of high concentrations of NaCl".
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.
The reactions believed to be catalyzed by channels of the Ca-ClC family are:
^Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ (October 2008). "TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity". Science. 322 (5901): 590–4. doi:10.1126/science.1163518. PMID18772398.
^Liu J, Liu Y, Ren Y, Kang L, Zhang L (March 2014). "Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-κB signaling pathway". Molecular Medicine Reports. 9 (3): 1068–74. doi:10.3892/mmr.2014.1888. PMID24401903.
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.
Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ (October 2008). "TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity". Science. 322 (5901): 590–4. doi:10.1126/science.1163518. PMID18772398.
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. doi:10.1038/nature07313. PMID18724360.