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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Huang, F; Zhang, H; Wu, M; Yang, H; Kudo, M; Peters, CJ; Woodruff, PG; Solberg, OD; Donne, ML; Huang, X; Sheppard, D; Fahy, JV; Wolters, PJ; Hogan, BLM; Finkbeiner, WE; Li, M; Jan, Y-N; Jan, LY; Rock, JR

Published Date

  • October 2, 2012

Published In

Volume / Issue

  • 109 / 40

Start / End Page

  • 16354 - 16359

PubMed ID

  • 22988107

Pubmed Central ID

  • 22988107

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1214596109

Language

  • eng

Conference Location

  • United States