Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction.
Journal Article (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
- PMC3479591
Electronic International Standard Serial Number (EISSN)
- 1091-6490
Digital Object Identifier (DOI)
- 10.1073/pnas.1214596109
Language
- eng
Conference Location
- United States