Editors' ChoicePhysiology

Hypoxia smells like lactate

Sci. Signal.  17 Nov 2015:
Vol. 8, Issue 403, pp. ec339
DOI: 10.1126/scisignal.aad8634

In response to hypoxia, the oxygen-sensitive glomus cells of the carotid body release neurotransmitters that activate the carotid sinus nerve to increase breathing. Chang et al. found that the olfactory receptor Olfr78 acts as the oxygen sensor in glomus cells. Olfr78 transcripts were enriched in the carotid body, and a fluorescent Olfr78 reporter was expressed in the glomus cells but not in other cells implicated in oxygen sensing. Mice lacking Olfr78 breathed normally under normoxic conditions, but they failed to increase their respiratory rate when placed in a hypoxic environment. In contrast, Olfr78–/– mice increased their respiratory rate in response to hypercapnia (increased CO2), implying that the mutants were unable to adjust breathing specifically in response to decreased O2. By marker gene expression and morphological criteria, glomus cells were normal in Olfr78–/– mice. Hypoxia stimulated the activity of the carotid sinus nerve in carotid bodies explanted from wild-type mice but not in carotid bodies from Olfr78–/– mice. Experiments in HEK293T cells demonstrated that physiologically relevant concentrations of lactate, a metabolite that rapidly increases in abundance during hypoxia, activated Olfr78. Activation of Olfr78, like many other G protein–coupled receptors, releases calcium from intracellular stores. Carotid bodies isolated from mice expressing a fluorescent calcium indicator in glomus cells exhibited calcium transients in response to hypoxia or application of lactate. Although hypoxia or application of lactate stimulated activity of the carotid sinus nerve in carotid body explants from wild-type mice, neither stimulated the nerve in carotid bodies from Olfr78–/– mice. Thus, the lactate that accumulates in the blood under low-oxygen conditions binds and activates Olfr78, thereby enabling glomus cells of the carotid body to sense hypoxia and stimulate breathing.

A. J. Chang, F. E. Ortega, J. Riegler, D. V. Madison, M. A. Krasnow, Oxygen regulation of breathing through an olfactory receptor activated by lactate. Nature 527, 240–244 (2015). [PubMed]