TY - JOUR
T1 - Calcium-activated chloride channel TMEM16A modulates mucin secretion and airway smooth muscle contraction
AU - Huang, Fen
AU - Zhang, Hongkang
AU - Wu, Meng
AU - Yang, Huanghe
AU - Kudo, Makoto
AU - Peters, Christian J.
AU - Woodruff, Prescott G.
AU - Solberg, Owen D.
AU - Donne, Matthew L.
AU - Huang, Xiaozhu
AU - Sheppard, Dean
AU - Fahy, John V.
AU - Wolters, Paul J.
AU - Hogan, Brigid L.M.
AU - Finkbeiner, Walter E.
AU - Li, Min
AU - Jan, Yuh Nung
AU - Jan, Lily Yeh
AU - Rock, Jason R.
PY - 2012/10/2
Y1 - 2012/10/2
N2 - 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.
AB - 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.
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U2 - 10.1073/pnas.1214596109
DO - 10.1073/pnas.1214596109
M3 - Article
C2 - 22988107
AN - SCOPUS:84867067619
SN - 0027-8424
VL - 109
SP - 16354
EP - 16359
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 40
ER -