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PMID: 22988107 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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 ·Vol. 109 ·No. 40 ·2012-10-02 ·Pages 16354-9

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

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.

MeSH Terms
Animals Anoctamin-1 Cells, Cultured Chloride Channels/metabolism Epithelial Cells/metabolism Humans Immunohistochemistry Mice Microscopy, Fluorescence Mucins/metabolism Muscle Contraction/physiology Muscle, Smooth/physiology Respiratory System/cytology,metabolism
Chemicals
ANO1 protein, mouse Anoctamin-1 Chloride Channels Mucins
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Huang Fen
Howard Hughes Medical Institute and Department of Physiology, University of California, San Francisco, CA 94158, USA.
Zhang Hongkang
Wu Meng
Yang Huanghe
Kudo Makoto
Peters Christian J
Woodruff Prescott G
Solberg Owen D
Donne Matthew L
Huang Xiaozhu
Sheppard Dean
Fahy John V
Wolters Paul J
Hogan Brigid L M
Finkbeiner Walter E
Li Min
Jan Yuh-Nung
Jan Lily Yeh
Rock Jason R
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1214596109
Published
2012-10-02
Epub
2012-00-17
Pages
16354-9
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC3479591
Subset
IM
Grants
NIMH NIH HHS · U54 MH084691 · United States
NINDS NIH HHS · R01 NS069229 · United States
NHLBI NIH HHS · P01 HL107202 · United States
Howard Hughes Medical Institute · United States
NIDA NIH HHS · R03DA031670 · United States
NIDA NIH HHS · R03 DA031670 · United States
NICHD NIH HHS · T32HD007470 · United States
NIMH NIH HHS · U54MH084691 · United States
NICHD NIH HHS · T32 HD007470 · United States
External Links
PubMed source DOI: 10.1073/pnas.1214596109 PMC Full Text View journal details
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