The odorant receptor OR2W3 on airway smooth muscle evokes bronchodilation via a cooperative chemosensory tradeoff between TMEM16A and CFTR.
In: Proceedings of the National Academy of Sciences of the United States of America, Jg. 117 (2020-11-10), Heft 45, S. 28485-28495
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Zugriff:
The recent discovery of sensory (tastant and odorant) G proteincoupled 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. [ABSTRACT FROM AUTHOR]
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The odorant receptor OR2W3 on airway smooth muscle evokes bronchodilation via a cooperative chemosensory tradeoff between TMEM16A and CFTR.
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Autor/in / Beteiligte Person: | Huang, Jessie ; Lam, Hong ; Koziol-White, Cynthia ; Limjunyawong, Nathachit ; Kim, Donghwa ; Kim, Nicholas ; Karmacharya, Nikhil ; Rajkumar, Premraj ; Firer, Danielle ; Dalesio, Nicholas M. ; Jude, Joseph ; Kurten, Richard C. ; Pluznick, Jennifer L. ; Deshpande, Deepak A. ; Penn, Raymond B. ; Liggett, Stephen B. ; Panettieri Jr, Reynold A. ; Dong, Xinzhong ; An, Steven S. |
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Zeitschrift: | Proceedings of the National Academy of Sciences of the United States of America, Jg. 117 (2020-11-10), Heft 45, S. 28485-28495 |
Veröffentlichung: | 2020 |
Medientyp: | academicJournal |
ISSN: | 0027-8424 (print) |
DOI: | 10.1073/pnas.2003111117 |
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