Document Type
Article
Publication Date
11-10-2020
Abstract
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.
Recommended Citation
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, Reynold A; Dong, Xinzhong; and An, Steven S, "The odorant receptor OR2W3 on airway smooth muscle evokes bronchodilation via a cooperative chemosensory tradeoff between TMEM16A and CFTR." (2020). Center for Translational Medicine Faculty Papers. Paper 77.
https://jdc.jefferson.edu/transmedfp/77
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
33097666
Language
English
Comments
This is the final published version of the paper in Proceedings of the National Academy of Sciences of the United States of America, 2020 Nov 10;117(45):28485-28495.
The article can also be accessed at the publishers website: https://doi.org/10.1073/pnas.2003111117
Copyright. The Authors