Loss of TMEM16A causes a defect in epithelial Ca2+-dependent chloride transport.
Molecular identification of the Ca(2+)-dependent chloride channel TMEM16A (ANO1) provided a fundamental step in understanding Ca(2+)-dependent Cl(-) secretion in epithelia. TMEM16A is an intrinsic constituent of Ca(2+)-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 Ca(2+)-dependent agonists is missing in mice lacking expression of TMEM16A. Ca(2+)-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(-/-) animals. Measurement of particle transport on the surface of tracheas ex vivo indicated largely reduced mucociliary clearance in TMEM16A(-/-) mice. These results clearly demonstrate the broad physiological role of TMEM16A(-/-) for Ca(2+)-dependent Cl(-) secretion and provide the basis for novel treatments in cystic fibrosis, infectious diarrhea, and Sjöegren syndrome.
Ousingsawat
Jiraporn
J
Institut für Physiologie, Universität Regensburg, Universitätsstrasse 31, D-93053 Regensburg, Germany.
Martins
Joana R
JR
Schreiber
Rainer
R
Rock
Jason R
JR
Harfe
Brian D
BD
Kunzelmann
Karl
K
D000818:Animals; D000075369:Anoctamin-1; D002118:Calcium / Q000737:chemistry; D018118:Chloride Channels / Q000737:chemistry* / Q000378:metabolism; D002712:Chlorides / Q000737:chemistry / Q000378:metabolism*; D003106:Colon / Q000473:pathology; D000242:Cyclic AMP / Q000378:metabolism; D004573:Electrolytes; D004847:Epithelial Cells / Q000166:cytology; D022781:Hepatocytes / Q000166:cytology; D017136:Ion Transport; D051379:Mice; D018345:Mice, Knockout; D014132:Trachea / Q000166:cytology
C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D002712:Chlorides; D004573:Electrolytes; D000242:Cyclic AMP; D002118:Calcium
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