Oxygen regulation of breathing through an olfactory receptor activated by lactate

Abstract

SummaryAnimals have evolved homeostatic responses to changes in oxygen availability that act on different time scales. Although the hypoxia-inducible factor (HIF) transcriptional pathway that controls long term responses to low oxygen (hypoxia) has been established1, the pathway that mediates acute responses to hypoxia in mammals is not well understood. Here we show that the olfactory receptor Olfr78 is highly and selectively expressed in oxygen-sensitive glomus cells of the carotid body, a chemosensory organ at the carotid artery bifurcation that monitors blood oxygen and stimulates breathing within seconds when oxygen declines2. Olfr78 mutants fail to increase ventilation in hypoxia but respond normally to hypercapnia. Glomus cells are present in normal numbers and appear structurally intact, but hypoxia-induced carotid body activity is diminished. Lactate, a metabolite that rapidly accumulates in hypoxia and induces hyperventilation3–6, activates Olfr78 in heterologous expression experiments, induces calcium transients in glomus cells, and stimulates carotid sinus nerve activity through Olfr78. We propose that in addition to its role in olfaction, Olfr78 acts as a hypoxia sensor in the breathing circuit by sensing lactate produced when oxygen levels decline.

Involvement of the metabolic sensor GPR81 in cardiovascular control

“…Even the established antilipolytic effect of GPR81 agonism may represent an appropriate response in this situation, by limiting FFA availability and thereby optimizing the use of oxygen for ATP production (45). Such a novel whole-body homeostatic mechanism is perhaps not that surprising given recent evidence that lactate sensing by another GPCR, Olfr78, plays a critical role in the carotid body by sensing hypoxia and breathing regulation (46). Locally in the kidney, vasoconstriction in response to physiological or pathophysiological GPR81 agonism seems incompatible with blood flow autoregulation and tissue survival.…”

Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences

“…Throughout this manuscript, we utilize two simulated data sets and four experimental data sets (Bottomly 14 [ Data set 3], GSE64570 15 [ Data set 4], GSE69244 16 [ Data set 5], GSE72165 17 [ Data set 6], see Supplementary File 1 for further details) for illustration. Details on the data generation and full records of the analyses are provided in the data sets and Supplementary File 1.…”

Olfactory receptor 544 reduces adiposity by steering fuel preference toward fats

“…Recent studies have highlighted the finding that ORs have diverse functions in various tissues in connection to several physiological contexts beyond odor recognition: MOR17-4 controls cellular motility and chemotaxis in sperm cells (5); OR1A1 modulates hepatic triglyceride metabolism in human hepatocytes through the PKA signaling pathway (6); Olfr78 functions as a renal short-chain fatty acid receptor involved in the regulation of renin secretion and blood pressure in the renal juxtaglomerular apparatus (7) and as a hypoxia sensor in the breathing circuit and stimulator of carotid sinus nerve activity in response to lactate in glomus cells (8); and MOR23 mediates signal transduction in myocytes for muscle regeneration and repair in skeletal muscle (9). These reports suggest that the diverse functions of ORs might include the regulation of energy metabolism; however, the roles of ORs in metabolic tissues are largely unknown.…”