期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 117, 期 45, 页码 28485-28495出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2003111117
关键词
olfactory receptor; G proteins; airway smooth muscle; single-cell analysis; asthma
资金
- New Jersey Alliance for Clinical and Translational Science [UL1TR0030117]
- National Institutes of Health [P01HL114471, R01HL137030, R01HL058506, R01NS054791, R01AI135186]
- Johns Hopkins University
- Patrick C. Walsh Prostate Cancer Research Fund from the James Buchanan Brady Urological Institute
- Maryland Cigarette Restitution Fund from the State of Maryland Department of Health and Mental Hygiene
The recent discovery of sensory (tastant and odorant) G protein -coupled receptors on the smooth muscle of human bronchi suggests unappreciated therapeutic targets in the management of obstructive lung diseases. Here we have characterized the effects of a wide range of volatile odorants on the contractile state of airway smooth muscle (ASM) and uncovered a complex mechanism of odorant-evoked signaling properties that regulate excitation-contraction (E-C) coupling in human ASM cells. Initial studies established multiple odorous molecules capable of increasing intracellular calcium ([Ca2+](i)) in ASM cells, some of which were (paradoxically) associated with ASM relaxation. Subsequent studies showed a terpenoid molecule (nerol)-stimulated OR2W3 caused increases in [Ca2+](i) and relaxation of ASM cells. Of note, OR2W3-evoked [Ca2+](i) mobilization and ASM relaxation required Ca2+ flux through the store-operated calcium entry (SOCE) pathway and accompanied plasma membrane depolarization. This chemosensory odorant receptor response was not mediated by adenylyl cyclase (AC)/cyclic nucleotide-gated (CNG) channels or by protein kinase A (PKA) activity. Instead, ASM olfactory responses to the monoterpene nerol were predominated by the activity of Ca2+-activated chloride channels (TMEM16A), including the cystic fibrosis transmembrane conductance regulator (CFTR) expressed on endo(sarco)plasmic reticulum. These findings demonstrate compartmentalization of Ca2+ signals dictates the odorant receptor OR2W3-induced ASM relaxation and identify a previously unrecognized E-C coupling mechanism that could be exploited in the development of therapeutics to treat obstructive lung diseases.
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