Defining an olfactory receptor function in airway smooth muscle cells

Abstract

Pathways that control, or can be exploited to alter, the increase in airway smooth muscle (ASM) mass and cellular remodeling that occur in asthma are not well defined. Here we report the expression of odorant receptors (ORs) belonging to the superfamily of G-protein coupled receptors (GPCRs), as well as the canonical olfaction machinery (Golf and AC3) in the smooth muscle of human bronchi. In primary cultures of isolated human ASM, we identified mRNA expression for multiple ORs. Strikingly, OR51E2 was the most highly enriched OR transcript mapped to the human olfactome in lung-resident cells. In a heterologous expression system, OR51E2 trafficked readily to the cell surface and showed ligand selectivity and sensitivity to the short chain fatty acids (SCFAs) acetate and propionate. These endogenous metabolic byproducts of the gut microbiota slowed the rate of cytoskeletal remodeling, as well as the proliferation of human ASM cells. These cellular responses in vitro were found in ASM from non-asthmatics and asthmatics, and were absent in OR51E2-deleted primary human ASM. These results demonstrate a novel chemo-mechanical signaling network in the ASM and serve as a proof-of-concept that a specific receptor of the gut-lung axis can be targeted to treat airflow obstruction in asthma.

Microbial Short-Chain Fatty Acids and Blood Pressure Regulation

“…However, a study in 2016 did show evidence that β ionone is a functional ligand: this study demonstrated that cells natively expressing OR51E2 exhibited an increase in intracellular calcium in response to β ionone which was negated by transfection of siRNA for OR51E2 (27). In late 2015, it was reported that Olfr78 responded to lactate in addition to acetate and propionate(28), and this was confirmed by two other groups in 2016 (29, 30). Notably, microbial metabolism also contributes to circulating lactate levels.…”

“…Notably, microbial metabolism also contributes to circulating lactate levels. Lactate, however, is a partial agonist of Olfr78 (acetate/propionate are full agonists), and is a ligand for (murine) Olfr78 but not for (human) OR51E2 (29). The reported EC50 of lactate has varied between different reports, from reported EC50’s of ~4 mM (28) vs. ~ 21 mM (29).…”

“…Lactate, however, is a partial agonist of Olfr78 (acetate/propionate are full agonists), and is a ligand for (murine) Olfr78 but not for (human) OR51E2 (29). The reported EC50 of lactate has varied between different reports, from reported EC50’s of ~4 mM (28) vs. ~ 21 mM (29). Therefore, although the ligand profile of this receptor has been fairly well studied, there still is not a clear consensus on which ligands are most physiologically relevant.…”

Olfactory receptor accessory proteins play crucial roles in receptor function and gene choice

“…One well-established example of a functional OR outside the olfactory system is Olfr78 (also known as MOR18-2) and its human ortholog OR51E2, which have been reported to function in the prostate, airway and kidney as well as the carotid body (Aisenberg et al, 2016; Chang et al, 2015; Wang et al, 2006; Pluznick et al, 2013). This receptor is an oOR and is trafficked to the cell surface in heterologous cells without the RTPs (Zhou et al, 2016; Pluznick et al, 2011; Neuhaus et al, 2009).…”

Acute oxygen sensing by the carotid body: a rattlebag of molecular mechanisms

“…At least two laboratories have reported that Olfr 78 was only sensitive to lactate outside the physiological range (Aisenberg et al . ; Zhou et al . ).…”