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: Wan Namkung, Zhen Yao, Walter E Finkbeiner, A S Verkman
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 25 Issue 11 Pg. 4048-62 (Nov 2011) ISSN: 1530-6860 [Electronic] United States
• PMID: 21836025 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• ANO1 protein, human
• Anoctamin-1
• Calcium Channel Agonists
• Chloride Channels
• Chlorides
• Neoplasm Proteins

Topics

• Animals
• Anoctamin-1
• Calcium Channel Agonists (pharmacology)
• Cells, Cultured
• Chloride Channels (drug effects)
• Chlorides (metabolism)
• Cystic Fibrosis (physiopathology)
• Gastrointestinal Motility (drug effects)
• Humans
• Mice
• Muscle Contraction (drug effects)
• Neoplasm Proteins (drug effects)
• Patch-Clamp Techniques