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Calcium-dependent chloride channel

Tmem16a EMD-3860.png
Cartoon representation of a mTMEM16A chloride channel based on a cryoelectron microscopy reconstruction.[1]
OPM superfamily369

The Calcium-Dependent Chloride Channel (Ca-ClC) proteins (or calcium-activated chloride channels (CaCCs),[2] 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),[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 gastrointestinal interstitial cells of Cajal, which are proteins which serve as intestinal pacemakers for peristalsis.[6] In addition to their role as chloride channels some CLCA proteins function as adhesion molecules and may also have roles as tumour suppressors.[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 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).[11] Mice lacking both channels lack hair cell mechanosensory potentials.[12] 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.[13] 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".[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]

Cl (out) ⇌ Cl (in)


Cations (e.g., Ca2+) (out) ⇌ Cations (e.g., Ca2+) (in)

In humans

CaCCs that are known to occur in humans include:

See also


  1. ^ The anoctamins are only expressed in eukaryotes, with 10 members in vertebrates.[7] Although all anoctamins are calcium-activated, not all members of this family are ion channels like ANO1; some are phospholipid 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 and Saccharomyces cerevisiae, respsectively.[7]


  1. ^ PDB: 5oyb​; Paulino C, Kalienkova V, Lam A, Neldner Y, Dutzler R (December 2017). "Activation mechanism of the calcium-activated chloride channel TMEM16A revealed by cryo-EM". Nature. 552 (7685): 421–425. doi:10.1038/nature24652. PMID 29236691.
  2. ^ Hartzell C, Putzier I, Arreola J (March 2005). "Calcium-activated chloride channels". Annual Review of Physiology. 67: 719–58. doi:10.1146/annurev.physiol.67.032003.154341. PMID 15709976.closed access
  3. ^ "CLCA1 chloride channel accessory 1 [Homo sapiens (human)]". Gene. National Center for Biotechnology Information. 13 January 2015.
  4. ^ a b Kunzelmann K, Kongsuphol P, Chootip K, Toledo C, Martins JR, Almaca J, Tian Y, Witzgall R, Ousingsawat J, Schreiber R (January 2011). "Role of the Ca2+ -activated Cl- channels bestrophin and anoctamin in epithelial cells". Biological Chemistry. 392 (1–2): 125–34. doi:10.1515/BC.2011.010. PMID 21194364.
  5. ^ a b Kunzelmann K, Kongsuphol P, Aldehni F, Tian Y, Ousingsawat J, Warth R, Schreiber R (October 2009). "Bestrophin and TMEM16-Ca(2+) activated Cl(-) channels with different functions". Cell Calcium. 46 (4): 233–41. doi:10.1016/j.ceca.2009.09.003. PMID 19783045.
  6. ^ a b Sanders KM, Zhu MH, Britton F, Koh SD, Ward SM (February 2012). "Anoctamins and gastrointestinal smooth muscle excitability". Experimental Physiology. 97 (2): 200–6. doi:10.1113/expphysiol.2011.058248. PMC 3272164. PMID access
  7. ^ a b c d e Brunner JD, Lim NK, Schenck S, Duerst A, Dutzler R (December 2014). "X-ray structure of a calcium-activated TMEM16 lipid scramblase". Nature. 516 (7530): 207–12. doi:10.1038/nature13984. PMID 25383531.
  8. ^ Evans SR, Thoreson WB, Beck CL (October 2004). "Molecular and functional analyses of two new calcium-activated chloride channel family members from mouse eye and intestine". The Journal of Biological Chemistry. 279 (40): 41792–800. doi:10.1074/jbc.M408354200. PMC 1383427. PMID 15284223.
  9. ^ 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. PMID 18772398.
  10. ^ 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. PMID 24151904.
  11. ^ Kim KX, Fettiplace R (January 2013). "Developmental changes in the cochlear hair cell mechanotransducer channel and their regulation by transmembrane channel-like proteins". The Journal of General Physiology. 141 (1): 141–8. doi:10.1085/jgp.201210913. PMC 3536526. PMID 23277480.
  12. ^ Kawashima Y, Géléoc GS, Kurima K, Labay V, Lelli A, Asai Y, Makishima T, Wu DK, Della Santina CC, Holt JR, Griffith AJ (December 2011). "Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes". The Journal of Clinical Investigation. 121 (12): 4796–809. doi:10.1172/JCI60405. PMC 3223072. PMID 22105175.
  13. ^ Smith CJ, Watson JD, Spencer WC, O'Brien T, Cha B, Albeg A, Treinin M, Miller DM (September 2010). "Time-lapse imaging and cell-specific expression profiling reveal dynamic branching and molecular determinants of a multi-dendritic nociceptor in C. elegans". Developmental Biology. 345 (1): 18–33. doi:10.1016/j.ydbio.2010.05.502. PMC 2919608. PMID 20537990.
  14. ^ Chatzigeorgiou M, Bang S, Hwang SW, Schafer WR (February 2013). "tmc-1 encodes a sodium-sensitive channel required for salt chemosensation in C. elegans". Nature. 494 (7435): 95–99. doi:10.1038/nature11845. PMC 4021456. PMID 23364694.
  15. ^ 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. PMID 24401903.
  16. ^ "1.A.17 The Calcium-Dependent Chloride Channel (Ca-ClC) Family". TCDB. Retrieved 16 April 2016.
  17. ^ a b "Calcium activated chloride channel". IUPHAR/BPS Guide to Pharmacology. Retrieved 7 October 2015.

Further reading

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