Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction

Fen Huang; Hongkang Zhang; Meng Wu; Huanghe Yang; Makoto Kudo; Christian J. Peters; Prescott G. Woodruff; Owen D. Solberg; Matthew L. Donne; Xiaozhu Huang; Dean Sheppard; John V. Fahy; Paul J. Wolters; Brigid L. M. Hogan; Walter E. Finkbeiner; Min Li; Yuh-Nung Jan; Lily Yeh Jan; Jason R. Rock

doi:10.1073/pnas.1214596109

Contributed by Lily Yeh Jan, August 23, 2012 (sent for review June 1, 2012)

Abstract

Mucous cell hyperplasia and airway smooth muscle (ASM) hyperresponsiveness are hallmark features of inflammatory airway diseases, including asthma. Here, we show that the recently identified calcium-activated chloride channel (CaCC) TMEM16A is expressed in the adult airway surface epithelium and ASM. The epithelial expression is increased in asthmatics, particularly in secretory cells. Based on this and the proposed functions of CaCC, we hypothesized that TMEM16A inhibitors would negatively regulate both epithelial mucin secretion and ASM contraction. We used a high-throughput screen to identify small-molecule blockers of TMEM16A-CaCC channels. We show that inhibition of TMEM16A-CaCC significantly impairs mucus secretion in primary human airway surface epithelial cells. Furthermore, inhibition of TMEM16A-CaCC significantly reduces mouse and human ASM contraction in response to cholinergic agonists. TMEM16A-CaCC blockers, including those identified here, may positively impact multiple causes of asthma symptoms.

Footnotes

↵¹To whom correspondence may be addressed. E-mail: jason.rock{at}ucsf.edu or lily.jan{at}ucsf.edu.

Author contributions: F.H., H.Z., M.W., H.Y., M.K., C.J.P., P.G.W., O.D.S., X.H., D.S., J.V.F., W.F., M.L., Y.-N.J., L.Y.J., and J.R.R. designed research; F.H., H.Z., M.W., H.Y., M.K., C.J.P., P.G.W., O.D.S., M.L.D., X.H., J.V.F., M.L., Y.-N.J., L.Y.J., and J.R.R. performed research; F.H., H.Z., M.W., H.Y., P.G.W., O.D.S., X.H., J.V.F., P.J.W., B.L.M.H., W.F., M.L., Y.-N.J., L.Y.J., and J.R.R. contributed new reagents/analytic tools; F.H., H.Z., M.W., H.Y., M.K., C.J.P., P.G.W., O.D.S., M.L.D., X.H., D.S., J.V.F., M.L., Y.-N.J., L.Y.J., and J.R.R. analyzed data; and F.H., C.J.P., Y.-N.J., L.Y.J., and J.R.R. wrote the paper.
The authors declare no conflict of interest.
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