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 (3-6), 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.

The carotid body is the major sensor of blood oxygen in mammals. It is stimulated by a reduction in arterial blood oxygen from 100 mmHg to <80 mmHg (1 mmHg = 133.3 Pa). A current model is that hypoxia causes closure of [K.sup.+] channels of glomus cells, stimulating [Ca.sup.2+]-dependent release of neurotransmitters onto afferent nerves that signal to brainstem respiratory centres. However, the oxygen sensor and sensing mechanism that trigger these events in glomus cells remain controversial (2) (Extended Data Fig. 1a-d). To identify new candidate molecules involved in carotid body oxygen sensing, we used RNA sequencing and whole-genome microarrays to compare gene expression of the carotid body from wild-type adult C57BL/6J mice with that of the adrenal medulla, which shares developmental and functional similarities with the carotid body but does not respond acutely to hypoxia (7). We reasoned that an oxygen sensor would be expressed at high levels in carotid body relative to adrenal medulla, and focused on signalling molecules that can act on the acute timescale of carotid body sensing. Transcripts for the olfactory receptor Olfr78 were highly expressed in carotid body (top 4% of all genes by RNA sequencing) and highly enriched relative to adrenal medulla by both RNA sequencing (92-fold) and microarrays (three probe sets, 17- to 80-fold) (Fig. 1a, b, Extended Data Fig. 2a-d, and Extended Data Table 1).

Olfactory receptors (ORs) comprise a subfamily of G-protein-coupled receptors that is the largest gene family in vertebrates, encoded by ~1,200 genes in mouse (8). ORs are expressed in olfactory sensory neurons and detect volatile odorants in smell. However, some ORs are expressed in other tissues (8-10). The RNA sequencing results showed that three other OR genes (Olfr1033, Olfr613, and Olfr856ps1) were expressed (reads per kilobase per million (RPKM) > 2) in the carotid body, but at similar levels in adrenal medulla and thus not pursued further (Fig. 1b and Extended Data Fig. 2b). Olfr558...