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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)16354-16359
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number40
DOIs
StatePublished - Oct 2 2012

ASJC Scopus subject areas

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    Huang, F., Zhang, H., Wu, M., Yang, H., Kudo, M., Peters, C. J., Woodruff, P. G., Solberg, O. D., Donne, M. L., Huang, X., Sheppard, D., Fahy, J. V., Wolters, P. J., Hogan, B. L. M., Finkbeiner, W. E., Li, M., Jan, Y. N., Jan, L. Y., & Rock, J. R. (2012). Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction. Proceedings of the National Academy of Sciences of the United States of America, 109(40), 16354-16359. https://doi.org/10.1073/pnas.1214596109