TMEM16A confers receptor-activated calcium-dependent chloride conductance

Abstract

Calcium (Ca²⁺)-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 Ca²⁺-activated chloride channel that is activated by intracellular Ca²⁺ and Ca²⁺-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 Ca²⁺-activated chloride currents. ANO1 is expressed in various secretory epithelia, the retina and sensory neurons. Furthermore, knockdown of mouse Ano1 markedly reduced native Ca²⁺-activated chloride currents as well as saliva production in mice. We conclude that ANO1 is a candidate Ca²⁺-activated chloride channel that mediates receptor-activated chloride currents in diverse physiological processes.