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Protease‐activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating
Author(s) -
McMahon Derek B.,
Workman Alan D.,
Kohanski Michael A.,
Carey Ryan M.,
Freund Jenna R.,
Hariri Benjamin M.,
Chen Bei,
Doghramji Laurel J.,
Adappa Nithin D.,
Palmer James N.,
Kennedy David W.,
Lee Robert J.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700114rrr
Subject(s) - mucociliary clearance , microbiology and biotechnology , mucus , receptor , respiratory epithelium , secretion , cystic fibrosis , cilium , apical membrane , airway , proteases , chemistry , immunology , biology , medicine , respiratory system , biochemistry , lung , membrane , anatomy , ecology , surgery , enzyme
Mucociliary clearance, driven by the engine of ciliary beating, is the primary physical airway defense against inhaled pathogens and irritants. A better understanding of the regulation of ciliary beating and mucociliary transport is necessary for identifying new receptor targets to stimulate improved clearance in airway diseases, such as cystic fibrosis and chronic rhinosinusitis. In this study, we examined the protease‐activated receptor (PAR)‐2, a GPCR previously shown to regulate airway cell cytokine and mucus secretion, and transepithelial Cl ‐ current. PAR‐ 2 is activated by proteases secreted by airway neutrophils and pathogens. We cultured various airway cell lines, primary human and mouse sinonasal cells, and human bronchial cells at air‐liquid interface and examined them using molecular biology, biochemistry, and live‐cell imaging. We found that PAR‐2 is expressed basolaterally, where it stimulates both intracellular Ca 2+ release and Ca 2+ influx, which activates low‐level nitric oxide production, increases apical membrane Cl _ permeability ∼3‐5‐fold, and increases ciliary beating ∼20‐50%. No molecular or functional evidence of PAR‐4 was observed. These data suggest a novel and previously overlooked role of PAR‐2 in airway physiology, adding to our understanding of the role of this receptor in airway Ca 2+ signaling and innate immunity.—McMahon, D. B., Workman, A. D., Kohanski, M. A., Carey, R. M., Freund, J. R., Hariri, B. M., Chen, B., Doghramji, L. J., Adappa, N. D., Palmer, J. N., Kennedy, D. W., Lee, R. J. Protease‐activated receptor 2 activates airway apical membrane chloride permeability and increases ciliary beating. FASEB J. 32, 155‐167 (2018). www.fasebj.org