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Research Article

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

Fen Huang, Hongkang Zhang, Meng Wu, Huanghe Yang, Makoto Kudo, Christian J. Peters, Prescott G. Woodruff, Owen D. Solberg, Matthew L. Donne, Xiaozhu Huang, Dean Sheppard, John V. Fahy, Paul J. Wolters, Brigid L. M. Hogan, Walter E. Finkbeiner, Min Li, Yuh-Nung Jan, Lily Yeh Jan, and Jason R. Rock
  1. aHoward Hughes Medical Institute and
  2. bDepartment of Physiology, University of California, San Francisco, CA 94158;
  3. cDepartment of Neuroscience, High Throughput Biology Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205;
  4. dLung Biology Center, Department of Medicine, University of California, San Francisco, CA 94158;
  5. eDepartment of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Kanazawa, Yokohama 236-0004, Japan;
  6. fDivision of Pulmonary and Critical Care Medicine, Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, CA 94143;
  7. Departments of gAnatomy,
  8. jPathology, and
  9. hMedicine, School of Medicine, University of California, San Francisco, CA 94143; and
  10. iDepartment of Cell Biology, Duke University Medical Center, Durham, NC 27710

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PNAS first published September 17, 2012; https://doi.org/10.1073/pnas.1214596109
Fen Huang
aHoward Hughes Medical Institute and
bDepartment of Physiology, University of California, San Francisco, CA 94158;
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Hongkang Zhang
cDepartment of Neuroscience, High Throughput Biology Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205;
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Meng Wu
cDepartment of Neuroscience, High Throughput Biology Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205;
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Huanghe Yang
aHoward Hughes Medical Institute and
bDepartment of Physiology, University of California, San Francisco, CA 94158;
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Makoto Kudo
dLung Biology Center, Department of Medicine, University of California, San Francisco, CA 94158;
eDepartment of Internal Medicine and Clinical Immunology, Yokohama City University Graduate School of Medicine, Kanazawa, Yokohama 236-0004, Japan;
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Christian J. Peters
aHoward Hughes Medical Institute and
bDepartment of Physiology, University of California, San Francisco, CA 94158;
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Prescott G. Woodruff
fDivision of Pulmonary and Critical Care Medicine, Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, CA 94143;
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Owen D. Solberg
fDivision of Pulmonary and Critical Care Medicine, Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, CA 94143;
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Matthew L. Donne
Departments of gAnatomy,
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Xiaozhu Huang
dLung Biology Center, Department of Medicine, University of California, San Francisco, CA 94158;
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Dean Sheppard
dLung Biology Center, Department of Medicine, University of California, San Francisco, CA 94158;
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John V. Fahy
fDivision of Pulmonary and Critical Care Medicine, Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, CA 94143;
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Paul J. Wolters
hMedicine, School of Medicine, University of California, San Francisco, CA 94143; and
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Brigid L. M. Hogan
iDepartment of Cell Biology, Duke University Medical Center, Durham, NC 27710
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Walter E. Finkbeiner
jPathology, and
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Min Li
cDepartment of Neuroscience, High Throughput Biology Center, School of Medicine, Johns Hopkins University, Baltimore, MD 21205;
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Yuh-Nung Jan
aHoward Hughes Medical Institute and
bDepartment of Physiology, University of California, San Francisco, CA 94158;
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Lily Yeh Jan
aHoward Hughes Medical Institute and
bDepartment of Physiology, University of California, San Francisco, CA 94158;
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  • For correspondence: jason.rock@ucsf.edu lily.jan@ucsf.edu
Jason R. Rock
Departments of gAnatomy,
hMedicine, School of Medicine, University of California, San Francisco, CA 94143; and
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  • For correspondence: jason.rock@ucsf.edu lily.jan@ucsf.edu
  1. Contributed by Lily Yeh Jan, August 23, 2012 (sent for review June 1, 2012)

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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.

Footnotes

  • ↵1To whom correspondence may be addressed. E-mail: jason.rock{at}ucsf.edu or lily.jan{at}ucsf.edu.
  • Author contributions: F.H., H.Z., M.W., H.Y., M.K., C.J.P., P.G.W., O.D.S., X.H., D.S., J.V.F., W.F., M.L., Y.-N.J., L.Y.J., and J.R.R. designed research; F.H., H.Z., M.W., H.Y., M.K., C.J.P., P.G.W., O.D.S., M.L.D., X.H., J.V.F., M.L., Y.-N.J., L.Y.J., and J.R.R. performed research; F.H., H.Z., M.W., H.Y., P.G.W., O.D.S., X.H., J.V.F., P.J.W., B.L.M.H., W.F., M.L., Y.-N.J., L.Y.J., and J.R.R. contributed new reagents/analytic tools; F.H., H.Z., M.W., H.Y., M.K., C.J.P., P.G.W., O.D.S., M.L.D., X.H., D.S., J.V.F., M.L., Y.-N.J., L.Y.J., and J.R.R. analyzed data; and F.H., C.J.P., Y.-N.J., L.Y.J., and J.R.R. wrote the paper.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1214596109/-/DCSupplemental.

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TMEM16A in asthma
Fen Huang, Hongkang Zhang, Meng Wu, Huanghe Yang, Makoto Kudo, Christian J. Peters, Prescott G. Woodruff, Owen D. Solberg, Matthew L. Donne, Xiaozhu Huang, Dean Sheppard, John V. Fahy, Paul J. Wolters, Brigid L. M. Hogan, Walter E. Finkbeiner, Min Li, Yuh-Nung Jan, Lily Yeh Jan, Jason R. Rock
Proceedings of the National Academy of Sciences Sep 2012, 201214596; DOI: 10.1073/pnas.1214596109

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TMEM16A in asthma
Fen Huang, Hongkang Zhang, Meng Wu, Huanghe Yang, Makoto Kudo, Christian J. Peters, Prescott G. Woodruff, Owen D. Solberg, Matthew L. Donne, Xiaozhu Huang, Dean Sheppard, John V. Fahy, Paul J. Wolters, Brigid L. M. Hogan, Walter E. Finkbeiner, Min Li, Yuh-Nung Jan, Lily Yeh Jan, Jason R. Rock
Proceedings of the National Academy of Sciences Sep 2012, 201214596; DOI: 10.1073/pnas.1214596109
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