title: Oxygen regulation of breathing through an olfactory receptor activated by lactate.
abstract: 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, 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. 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, 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.
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305-5307, USA.
authors.forename: Andy J
authors.initials: AJ
authors.lastname: Chang
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305-5307, USA.
authors.forename: Fabian E
authors.initials: FE
authors.lastname: Ortega
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Johannes
authors.initials: J
authors.lastname: Riegler
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Daniel V
authors.initials: DV
authors.lastname: Madison
authors.affiliation: Department of Biochemistry, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305-5307, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Krasnow
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002344:Carotid Body / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002346:Carotid Sinus / Q000294:innervation; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D006935:Hypercapnia / Q000235:genetics / Q000378:metabolism; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018034:Olfactory Receptor Neurons / Q000378:metabolism*; D010100:Oxygen / Q000097:blood / Q000378:metabolism*; D018035:Receptors, Odorant / Q000172:deficiency / Q000378:metabolism*; D012119:Respiration
chemical_list: C000603341:Olfr78 protein, mouse; D018035:Receptors, Odorant; D019344:Lactic Acid; D010100:Oxygen