title: Small-molecule activators of TMEM16A, a calcium-activated chloride channel, stimulate epithelial chloride secretion and intestinal contraction.
abstract: TMEM16A (ANO1) is a calcium-activated chloride channel (CaCC) expressed in secretory epithelia, smooth muscle, and other tissues. Cell-based functional screening of ∼110,000 compounds revealed compounds that activated TMEM16A CaCC conductance without increasing cytoplasmic Ca(2+). By patch-clamp, N-aroylaminothiazole "activators" (E(act)) strongly increased Cl(-) current at 0 Ca(2+), whereas tetrazolylbenzamide "potentiators" (F(act)) were not active at 0 Ca(2+) but reduced the EC(50) for Ca(2+)-dependent TMEM16A activation. Of 682 analogs tested, the most potent activator (E(act)) and potentiator (F(act)) produced large and more sustained CaCC Cl(-) currents than general agonists of Ca(2+) signaling, with EC(50) 3-6 μM and Cl(-) conductance comparable to that induced transiently by Ca(2+)-elevating purinergic agonists. Analogs of activators were identified that fully inhibited TMEM16A Cl(-) conductance, providing further evidence for direct TMEM16A binding. The TMEM16A activators increased CaCC conductance in human salivary and airway submucosal gland epithelial cells, and IL-4 treated bronchial cells, and stimulated submucosal gland secretion in human bronchi and smooth muscle contraction in mouse intestine. Small-molecule, TMEM16A-targeted activators may be useful for drug therapy of cystic fibrosis, dry mouth, and gastrointestinal hypomotility disorders, and for pharmacological dissection of TMEM16A function.
authors.affiliation: Department of Medicine and Physiology, University of California, San Francisco, California 94143-0521, USA.
authors.forename: Wan
authors.initials: W
authors.lastname: Namkung
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yao
authors.forename: Walter E
authors.initials: WE
authors.lastname: Finkbeiner
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D002478:Cells, Cultured; D018118:Chloride Channels / Q000187:drug effects*; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects; D006801:Humans; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009363:Neoplasm Proteins / Q000187:drug effects*; D018408:Patch-Clamp Techniques
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D002120:Calcium Channel Agonists; D018118:Chloride Channels; D002712:Chlorides; D009363:Neoplasm Proteins