Calcium-activated Chloride Channel TMEM16A Modulates Mucin Secretion and Airway Smooth Muscle Contraction

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2012 Sep 19

PMID 22988107

Citations 184

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

DTIAM: a unified framework for predicting drug-target interactions, binding affinities and drug mechanisms.

Lu Z, Song G, Zhu H, Lei C, Sun X, Wang K Nat Commun. 2025; 16(1):2548.

PMID: 40089473 DOI: 10.1038/s41467-025-57828-0.

Integrated proteogenomic characterization of ampullary adenocarcinoma.

Zhang Q, Xu X, Jiang D, Wang Y, Wang H, Zhu J Cell Discov. 2025; 11(1):2.

PMID: 39762212 PMC: 11704194. DOI: 10.1038/s41421-024-00742-4.

Tamsulosin ameliorates bone loss by inhibiting the release of Cl through wedging into an allosteric site of TMEM16A.

Li S, Sun W, Li S, Zhu L, Guo S, He J Proc Natl Acad Sci U S A. 2024; 122(1):e2407493121.

PMID: 39739807 PMC: 11725887. DOI: 10.1073/pnas.2407493121.

Distinct modulation of calcium-activated chloride channel TMEM16A by drug-binding sites.

Roh J, Gee H, Wainger B, Kim W, Lee W, Nam J Proc Natl Acad Sci U S A. 2024; 121(51):e2314011121.

PMID: 39656212 PMC: 11665900. DOI: 10.1073/pnas.2314011121.

The Tmem16a chloride channel is required for mucin maturation after secretion from goblet-like cells in the Xenopus tropicalis tadpole skin.

Dubaissi E, Hilton E, Lilley S, Collins R, Holt C, March P Sci Rep. 2024; 14(1):25555.

PMID: 39461969 PMC: 11514049. DOI: 10.1038/s41598-024-76482-y.

References

Nakano T, Inoue H, Fukuyama S, Matsumoto K, Matsumura M, Tsuda M . Niflumic acid suppresses interleukin-13-induced asthma phenotypes. Am J Respir Crit Care Med. 2006; 173(11):1216-21. DOI: 10.1164/rccm.200410-1420OC. View

Rock J, ONeal W, Gabriel S, Randell S, Harfe B, Boucher R . Transmembrane protein 16A (TMEM16A) is a Ca2+-regulated Cl- secretory channel in mouse airways. J Biol Chem. 2009; 284(22):14875-80. PMC: 2685669. DOI: 10.1074/jbc.C109.000869. View

Huang F, Rock J, Harfe B, Cheng T, Huang X, Jan Y . Studies on expression and function of the TMEM16A calcium-activated chloride channel. Proc Natl Acad Sci U S A. 2009; 106(50):21413-8. PMC: 2781737. DOI: 10.1073/pnas.0911935106. View

Ferrera L, Caputo A, Galietta L . TMEM16A protein: a new identity for Ca(2+)-dependent Cl⁻ channels. Physiology (Bethesda). 2010; 25(6):357-63. DOI: 10.1152/physiol.00030.2010. View

Rhoden K, Cianchetta S, Duchi S, Romeo G . Fluorescence quantitation of thyrocyte iodide accumulation with the yellow fluorescent protein variant YFP-H148Q/I152L. Anal Biochem. 2007; 373(2):239-46. DOI: 10.1016/j.ab.2007.10.020. View

Ordonez C, Khashayar R, Wong H, Ferrando R, Wu R, Hyde D . Mild and moderate asthma is associated with airway goblet cell hyperplasia and abnormalities in mucin gene expression. Am J Respir Crit Care Med. 2001; 163(2):517-23. DOI: 10.1164/ajrccm.163.2.2004039. View

Schroeder B, Cheng T, Jan Y, Jan L . Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell. 2008; 134(6):1019-29. PMC: 2651354. DOI: 10.1016/j.cell.2008.09.003. View

Nials A, Uddin S . Mouse models of allergic asthma: acute and chronic allergen challenge. Dis Model Mech. 2008; 1(4-5):213-20. PMC: 2590830. DOI: 10.1242/dmm.000323. View

Kudo M, Melton A, Chen C, Engler M, Huang K, Ren X . IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction. Nat Med. 2012; 18(4):547-54. PMC: 3321096. DOI: 10.1038/nm.2684. View

10.

Janssen L, Sims S . Ca(2+)-dependent Cl- current in canine tracheal smooth muscle cells. Am J Physiol. 1995; 269(1 Pt 1):C163-9. DOI: 10.1152/ajpcell.1995.269.1.C163. View

11.

Galietta L, Folli C, Caci E, Pedemonte N, Taddei A, Ravazzolo R . Effect of inflammatory stimuli on airway ion transport. Proc Am Thorac Soc. 2005; 1(1):62-5. DOI: 10.1513/pats.2306017. View

12.

Singer M, Martin L, Vargaftig B, Park J, Gruber A, Li Y . A MARCKS-related peptide blocks mucus hypersecretion in a mouse model of asthma. Nat Med. 2004; 10(2):193-6. DOI: 10.1038/nm983. View

13.

Hauber H, Goldmann T, Vollmer E, Wollenberg B, Hung H, Levitt R . LPS-induced mucin expression in human sinus mucosa can be attenuated by hCLCA inhibitors. J Endotoxin Res. 2007; 13(2):109-16. DOI: 10.1177/0968051907079168. View

14.

Diena T, Melani R, Caci E, Pedemonte N, Sondo E, Zegarra-Moran O . Block of CFTR-dependent chloride currents by inhibitors of multidrug resistance-associated proteins. Eur J Pharmacol. 2007; 560(2-3):127-31. PMC: 2692578. DOI: 10.1016/j.ejphar.2007.01.051. View

15.

Knight D . Talniflumate (Genaera). Curr Opin Investig Drugs. 2004; 5(5):557-62. View

16.

Choy D, Modrek B, Abbas A, Kummerfeld S, Clark H, Wu L . Gene expression patterns of Th2 inflammation and intercellular communication in asthmatic airways. J Immunol. 2010; 186(3):1861-9. PMC: 3981556. DOI: 10.4049/jimmunol.1002568. View

17.

Fahy J . Goblet cell and mucin gene abnormalities in asthma. Chest. 2002; 122(6 Suppl):320S-326S. DOI: 10.1378/chest.122.6_suppl.320s. View

18.

Galietta L, Haggie P, Verkman A . Green fluorescent protein-based halide indicators with improved chloride and iodide affinities. FEBS Lett. 2001; 499(3):220-4. DOI: 10.1016/s0014-5793(01)02561-3. View

19.

Perez-Ruiz F, Alonso-Ruiz A, Calabozo M, Herrero-Beites A, Garcia-Erauskin G, Ruiz-Lucea E . Efficacy of allopurinol and benzbromarone for the control of hyperuricaemia. A pathogenic approach to the treatment of primary chronic gout. Ann Rheum Dis. 1998; 57(9):545-9. PMC: 1752740. DOI: 10.1136/ard.57.9.545. View

20.

Teixeira M, Coelho R, Leal-Cardoso J, Criddle D . Comparative effects of niflumic acid and nifedipine on 5-hydroxytryptamine- and acetylcholine-induced contraction of the rat trachea. Eur J Pharmacol. 2000; 394(1):117-22. DOI: 10.1016/s0014-2999(00)00089-3. View