TMEM16A confers receptor-activated calcium-dependent chloride conductance

Abstract

Calcium (Ca(2+))-activated chloride channels are fundamental mediators in numerous physiological processes including transepithelial secretion, cardiac and neuronal excitation, sensory transduction, smooth muscle contraction and fertilization. Despite their physiological importance, their molecular identity has remained largely unknown. Here we show that transmembrane protein 16A (TMEM16A, which we also call anoctamin 1 (ANO1)) is a bona fide Ca(2+)-activated chloride channel that is activated by intracellular Ca(2+) and Ca(2+)-mobilizing stimuli. With eight putative transmembrane domains and no apparent similarity to previously characterized channels, ANO1 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with native Ca(2+)-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca(2+)-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca(2+)-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.

Cytogenetic and immunohistochemical characterization of mammary analogue secretory carcinoma of salivary glands

“…It was first described as a calcium-activated chloride channel in 2008 and is routinely used in the diagnosis of gastrointestinal stromal tumours (GIST) [10][11][12][13][14][15][16]. Its expression pattern in salivary gland neoplasms is not well established although a recent study showed expression in acinar lumens in both normal glands and ACC [13].…”

Activation of Ca2+‐activated Cl− channel ANO1 by localized Ca2+ signals

“…This, in combination with the low Ca 2+ sensitivity of ANO1 channels (EC 50 at negative voltages is ∼2–5 μ m; Yang et al . 2008; Xiao et al . 2011), would make them insensitive to ‘distal’ Ca 2+ elevations.…”

“…−60 to −100 mV) were reported to be in the range of 3–5 μ m while at high, depolarizing voltages the EC 50 is about tenfold lower (Yang et al . 2008; Xiao et al . 2011).…”

“…2008; Yang et al . 2008; Liu, 2014). Accordingly, ANO1 was found to mediate CaCC currents in epithelia and smooth muscles (Huang et al .…”

“…A topological model with at least eight transmembrane (TM) domains, cytosolic N‐ and C‐termini and a re‐entrant loop between TM5 and TM6 (probably pore‐lining) has been proposed (Yang et al . 2008; Ferrera et al . 2010) but structure–function relationship data for anoctamins are still sparse.…”