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

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.

Intracellular TMEM16A is necessary for myogenesis of skeletal muscle

“…The resultant activation of TMEM16A allows chloride to move into ER lumen and bind Ca 2+ , and hence the ER calcium release is inhibited. As a matter of fact, similar effect was observed in the case of intracellular CFTR (cystic fibrosis transmembrane conductance regulator) ( Benedetto et al., 2017 ; Divangahi et al., 2009 ; Huang et al., 2020 ).The intracellular CFTR promotes Ca 2+ influx to ER through facilitating the flux of chloride and its binding to Ca 2+ in the ER in smooth muscle cells. As CFTR is also expressed in skeletal muscle cells ( Divangahi et al., 2009 ), whether it is involved in the role of TMEM16A in ER calcium release remains to be determined in the future.…”

Platelet olfactory receptor activation limits platelet reactivity and growth of aortic aneurysms

“…Olfactory receptor signaling in nonolfactory tissue is a relatively new discovery but appears to regulate physiological processes, including blood pressure, fat metabolism, and airway hyperresponsiveness (34)(35)(36). Hereditary anosmia (the inability to smell using functional olfactory receptors) coexists in patients with dysfunctional platelet activity -an observation made many years ago that was never explored (37).…”

Epinephrine evokes shortening of human airway smooth muscle cells following β2adrenergic receptor desensitization

“…To ascertain whether EPI can act as a procontractile agonist via activating α 1 ARs expressed on HASM cells, we assessed single-cell calcium and single-cell shortening methods as surrogates for HASM contraction ( 37 ). Under experimental conditions that induce β 2 AR desensitization (as above), we found that pharmacological inhibition of α 1 ARs with DM significantly attenuated EPI-induced intracellular calcium mobilization ( Fig.…”

“…Magnetic twisting cytometry (MTC) was used to assess the single-cell contractility (i.e., HASM cellular contraction and relaxation), as previously described ( 34 , 36 , 37 ). Briefly, an RGD-coated ferrimagnetic microbead (4.5 μm in diameter) functionalized to the cytoskeleton through cell surface integrin receptors was magnetized and twisted by an external magnetic field that varied sinusoidally in time.…”