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

Proc Natl Acad Sci U S A. 2020 Nov 10;117(45):28485-28495. doi: 10.1073/pnas.2003111117. Epub 2020 Oct 23.


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.

Keywords: G proteins; airway smooth muscle; asthma; olfactory receptor; single-cell analysis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Anoctamin-1 / metabolism*
  • Bronchi / metabolism
  • Calcium / metabolism
  • Cells, Cultured
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Humans
  • Lung / metabolism
  • Muscle Contraction / physiology
  • Muscle Relaxation
  • Muscle, Smooth / metabolism*
  • Myocytes, Smooth Muscle / metabolism
  • Neoplasm Proteins / metabolism*
  • Receptors, Odorant / genetics
  • Receptors, Odorant / metabolism*


  • ANO1 protein, human
  • Anoctamin-1
  • CFTR protein, human
  • Neoplasm Proteins
  • OR2W3 protein, human
  • Receptors, Odorant
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Adenylyl Cyclases
  • Calcium