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

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.

Pubmed ID: 22988107


  • 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 BL
  • Finkbeiner WE
  • Li M
  • Jan YN
  • Jan LY
  • Rock JR


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

October 2, 2012

Associated Grants

  • Agency: NHLBI NIH HHS, Id: P01 HL107202
  • Agency: NINDS NIH HHS, Id: R01 NS069229
  • Agency: NIDA NIH HHS, Id: R03DA031670
  • Agency: NICHD NIH HHS, Id: T32HD007470
  • Agency: NIMH NIH HHS, Id: U54MH084691
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Cells, Cultured
  • Chloride Channels
  • Epithelial Cells
  • Humans
  • Immunohistochemistry
  • Mice
  • Microscopy, Fluorescence
  • Mucins
  • Muscle Contraction
  • Muscle, Smooth
  • Respiratory System