TMEM16A confers receptor-activated calcium-dependent chloride conductance

摘要

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, AN01 defines a new family of ionic channels. The biophysical properties as well as the pharmacological profile of ANO1 are in full agreement with na'tive Ca~(2+)-activated chloride currents. AN01 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 AN01 is a candidate Ca2 -activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.