The odorant receptor OR2W3 on airway smooth muscle evokes bronchodilation via a cooperative chemosensory tradeoff between TMEM16A and CFTR

Jessie Huang, Hong Lam, Cynthia Koziol-White, Nathachit Limjunyawong, Donghwa Kim, Nicholas Kim, Nikhil Karmacharya, Premraj Rajkumar, Danielle Firer, Nicholas M. Dalesio, Joseph Jude, Richard C. Kurten, Jennifer L. Pluznick, Deepak A. Deshpande, Raymond B. Penn, Stephen B. Liggett, Reynold A. Panettieri, Xinzhong Dong, Steven S. An

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)28485-28495
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number45
DOIs
StatePublished - Nov 10 2020

Keywords

  • Airway smooth muscle
  • Asthma
  • G proteins
  • Olfactory receptor
  • Single-cell analysis

ASJC Scopus subject areas

  • General

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