Calcium-dependent chloride channel

TMEM16

Crystal structure of the lipid scramblase nhTMEM16 in crystal form 1
Identifiers
Symbol ?
Pfam PF04547
InterPro IPR032394
TCDB 1.A.17
OPM superfamily 517
OPM protein 4wis

The Calcium-Dependent Chloride Channel (Ca-ClC) Family (TC# 1.A.17) consists of eukaryotic proteins that are required for normal electrolyte and fluid secretion, olfactory perception, and neuronal and smooth muscle excitability in animals.[1] 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). A representative list of proteins belonging to the Calcium-dependent chloride channel family can be found in the Transporter Classification Database.[2]

Function

All vertebrate cells regulate their cell volume by activating chloride channels thereby activating regulatory volume decrease. Almaça et al. (2009) showed that the Ca2+-activated Cl- channel TMEM16A (Anoctamin 1a) together with other TMEM16 proteins are activated by cell swelling through an autocrine mechanism that involves ATP release and binding to purinergic P2Y(2) receptors.[3] TMEM16A channels are activated by ATP through an increase in intracellular Ca2+ and a Ca2+-independent mechanism engaging extracellular-regulated protein kinases (ERK1/2). The ability of epithelial cells to activate a Cl- conductance upon cell swelling, and to decrease their cell volume was dependent on TMEM16 proteins. Activation was reduced in the colonic epithelium and in salivary acinar cells from mice lacking expression of TMEM16A. Thus, TMEM16 proteins appear to be a crucial component of epithelial volume-regulated Cl- channels and may also have a function during proliferation and apoptotic cell death.[3]

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).[4] Mice lacking both channels lack hair cell mechanosensory potentials.[5] 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.[6] 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.[7]

Ion channels promote the development and progression of tumors. 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.[8]

The calcium-activated chloride channel anoctamin1 (ANO1; TMEM16A) is fundamental for the function of epithelial organs, and mice lacking ANO1 expression exhibit transport defects and a pathology similar to that of cystic fibrosis. They also show a general defect of epithelial electrolyte transport.[9]

The reactions believed to be catalyzed by channels of the Ca-ClC family are:[2]

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

Mutations

Channelopathies, defined as diseases that are caused by mutations in genes encoding ion channels, are associated with a wide variety of symptoms. Impaired chloride transport can cause diseases as diverse as cystic fibrosis, myotonia, epilepsy, hyperekplexia, lysosomal storage disease, deafness, renal salt loss, kidney stones and osteopetrosis. These disorders are caused by mutations in genes belonging to non-related gene families, including CLC chloride channels and GABA- and glycine receptors.[10]

Mutations in transmembrane channel-like gene 1 (TMC1/Tmc1; TC# 1.A.17.4.6) cause dominant or recessive hearing loss in humans and mice. Tmc1 mRNA is specifically expressed in neurosensory hair cells of the inner ear. Cochlear neurosensory hair cells of Tmc1 mutant mice fail to mature into fully functional sensory receptors and exhibit concomitant structural degeneration that could be a cause or an effect of the maturational defect. The molecular and cellular functions of TMC1 protein are substantially unknown due, at least in part, to in situ expression levels that are prohibitively low for direct biochemical analysis.[11]

See also

Further reading

References

  1. ↑ Pang, Chunli; Yuan, Hongbo; Ren, Shuxi; Chen, Yafei; An, Hailong; Zhan, Yong (2014-01-01). "TMEM16A/B associated CaCC: structural and functional insights". Protein and Peptide Letters 21 (1): 94–99. ISSN 1875-5305. PMID 24151904.
  2. 1 2 "1.A.17 The Calcium-Dependent Chloride Channel (Ca-ClC) Family". TCDB. Retrieved 2016-04-16.
  3. 1 2 Almaça, Joana; Tian, Yuemin; Aldehni, Fadi; Ousingsawat, Jiraporn; Kongsuphol, Patthara; Rock, Jason R.; Harfe, Brian D.; Schreiber, Rainer; Kunzelmann, Karl (2009-10-16). "TMEM16 proteins produce volume-regulated chloride currents that are reduced in mice lacking TMEM16A". The Journal of Biological Chemistry 284 (42): 28571–28578. doi:10.1074/jbc.M109.010074. ISSN 1083-351X. PMC 2781400. PMID 19654323.
  4. ↑ Kim, Kyunghee X.; Fettiplace, Robert (2013-01-01). "Developmental changes in the cochlear hair cell mechanotransducer channel and their regulation by transmembrane channel-like proteins". The Journal of General Physiology 141 (1): 141–148. doi:10.1085/jgp.201210913. ISSN 1540-7748. PMC 3536526. PMID 23277480.
  5. ↑ Kawashima, Yoshiyuki; Géléoc, Gwenaëlle S. G.; Kurima, Kiyoto; Labay, Valentina; Lelli, Andrea; Asai, Yukako; Makishima, Tomoko; Wu, Doris K.; Della Santina, Charles C. (2011-12-01). "Mechanotransduction in mouse inner ear hair cells requires transmembrane channel-like genes". The Journal of Clinical Investigation 121 (12): 4796–4809. doi:10.1172/JCI60405. ISSN 1558-8238. PMC 3223072. PMID 22105175.
  6. ↑ Smith, Cody J.; Watson, Joseph D.; Spencer, W. Clay; O'Brien, Tim; Cha, Byeong; Albeg, Adi; Treinin, Millet; Miller, David M. (2010-09-01). "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. ISSN 1095-564X. PMC 2919608. PMID 20537990.
  7. ↑ Chatzigeorgiou, Marios; Bang, Sangsu; Hwang, Sun Wook; Schafer, William R. (2013-02-07). "tmc-1 encodes a sodium-sensitive channel required for salt chemosensation in C. elegans". Nature 494 (7435): 95–99. doi:10.1038/nature11845. ISSN 1476-4687. PMC 4021456. PMID 23364694.
  8. ↑ Liu, Jun; Liu, Yu; Ren, Yingang; Kang, Li; Zhang, Lihua (2014-03-01). "Transmembrane protein with unknown function 16A overexpression promotes glioma formation through the nuclear factor-κB signaling pathway". Molecular Medicine Reports 9 (3): 1068–1074. doi:10.3892/mmr.2014.1888. ISSN 1791-3004. PMID 24401903.
  9. ↑ Schreiber, Rainer; Uliyakina, Inna; Kongsuphol, Patthara; Warth, Richard; Mirza, Myriam; Martins, Joana R.; Kunzelmann, Karl (2010-03-05). "Expression and function of epithelial anoctamins". The Journal of Biological Chemistry 285 (10): 7838–7845. doi:10.1074/jbc.M109.065367. ISSN 1083-351X. PMC 2844227. PMID 20056604.
  10. ↑ Planells-Cases, Rosa; Jentsch, Thomas J. (2009-03-01). "Chloride channelopathies". Biochimica Et Biophysica Acta 1792 (3): 173–189. doi:10.1016/j.bbadis.2009.02.002. ISSN 0006-3002. PMID 19708126.
  11. ↑ Labay, Valentina; Weichert, Rachel M.; Makishima, Tomoko; Griffith, Andrew J. (2010-10-05). "Topology of transmembrane channel-like gene 1 protein". Biochemistry 49 (39): 8592–8598. doi:10.1021/bi1004377. ISSN 1520-4995. PMC 3005947. PMID 20672865.

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