Calcium dependent chloride channel

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. 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.

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.

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.

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.

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

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.

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.