Loss of TMEM16A causes a defect in epithelial Ca2+ -dependent chloride transport

Abstract

Molecular identification of the Ca2+-dependent chloride channel TMEM16A (AN01) provided a fundamental step in understanding Ca2+-dependent Cl- secretion in epithelia. TMEM16A is an intrinsic constituent of Ca2+-dependent Cl- channels in cultured epithelia and may control salivary output, but its physiological role in native epithelial tissues remains largely obscure. Here, we demonstrate that Cl- secretion in native epithelia activated by Ca2+-dependent agonists is missing in mice lacking expression of TMEM16A. Ca2+-dependent Cl-transport was missing or largely reduced in isolated tracheal and colonic epithelia, as well as hepatocytes and acinar cells from pancreatic and submandibular glands of TMEM16A-1- animals. Measurement of particle transport on the surface of tracheas ex vivo indicated largely reduced mucociliary clearance in TMEM16A-1- mice. These results clearly demonstrate the broad physiological role of TMEM16A-1- for Ca2+ -dependent Cl- secretion and provide the basis for novel treatments in cystic fibrosis, infectious diarrhea, and Sjöegren syndrome. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.