title: Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction.
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.
authors.affiliation: Howard Hughes Medical Institute and Department of Physiology, University of California, San Francisco, CA 94158, USA.
authors.forename: Fen
authors.initials: F
authors.lastname: Huang
authors.forename: Hongkang
authors.initials: H
authors.lastname: Zhang
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.forename: Huanghe
authors.initials: H
authors.lastname: Yang
authors.forename: Makoto
authors.initials: M
authors.lastname: Kudo
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Peters
authors.forename: Prescott G
authors.initials: PG
authors.lastname: Woodruff
authors.forename: Owen D
authors.initials: OD
authors.lastname: Solberg
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Donne
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: John V
authors.initials: JV
authors.lastname: Fahy
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
authors.forename: Brigid L M
authors.initials: BL
authors.lastname: Hogan
authors.forename: Walter E
authors.initials: WE
authors.lastname: Finkbeiner
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Yuh-Nung
authors.initials: YN
authors.lastname: Jan
authors.forename: Lily Yeh
authors.initials: LY
authors.lastname: Jan
authors.forename: Jason R
authors.initials: JR
authors.lastname: Rock
mesh_terms: D000818:Animals; D000075369:Anoctamin-1; D002478:Cells, Cultured; D018118:Chloride Channels / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008856:Microscopy, Fluorescence; D009077:Mucins / Q000378:metabolism*; D009119:Muscle Contraction / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D012137:Respiratory System / Q000166:cytology* / Q000378:metabolism*
chemical_list: C531181:ANO1 protein, mouse; D000075369:Anoctamin-1; D018118:Chloride Channels; D009077:Mucins