Oxygen regulation of breathing through an olfactory receptor activated by lactate

• Published in: Nature (London) Vol. 527; no. 7577; pp. 240 - 244
• Main Authors: Chang, Andy J., Ortega, Fabian E., Riegler, Johannes, Madison, Daniel V., Krasnow, Mark A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.11.2015; Nature Publishing Group
• Subjects: 631/378/2583; 631/378/340; 631/443/1784; Animals; Calcium Signaling; Carotid Body - cytology; Carotid Body - drug effects; Carotid Body - metabolism; Carotid Sinus - innervation; Female; Gene expression; Genomes; HEK293 Cells; Humanities and Social Sciences; Humans; Hypercapnia - genetics; Hypercapnia - metabolism; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Lactates; Lactic Acid - metabolism; Lactic Acid - pharmacology; letter; Metabolites; Mice; multidisciplinary; Olfaction; Olfactory Receptor Neurons - metabolism; Olfactory receptors; Oxygen; Oxygen - blood; Oxygen - metabolism; Physiological aspects; Physiological research; Receptors, Odorant - deficiency; Receptors, Odorant - metabolism; Respiration; Science; Signal transduction; Smooth muscle; Ventilation
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature15721

In addition to its role in olfaction, Olfr78 is involved in sensing hypoxia. A dual function olfactory receptor The G-protein-coupled receptor olfactory receptor 78 (Olfr78) is shown here to be involved in sensing hypoxia. The receptor is expressed in the carotid body, as well as in the nose. The receptor is activated by the lactate that accumulates when oxygen declines and Olfr78 null mouse mutants fail to increase breathing in hypoxia. This finding raises the possibility that synthetic agonists and antagonists of Olfr78 might be of use in the therapeutic control of breathing and other responses that it controls. Animals have evolved homeostatic responses to changes in oxygen availability that act on different timescales. Although the hypoxia-inducible factor (HIF) transcriptional pathway that controls long-term responses to low oxygen (hypoxia) has been established 1 , the pathway that mediates acute responses to hypoxia in mammals is not well understood. Here we show that the olfactory receptor gene 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 declines 2 . 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 hyperventilation 3 , 4 , 5 , 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.