Abstract
Carotid bodies (CBs) sense arterial blood O
2
levels. Hypoxemia activates the carotid sinus nerve (CSN) afferent activity to elicit cardiorespiratory reflexes to maintain tissue oxygenation. This brief review presents emerging evidence suggesting that CBs employ distinct O
2
-sensing mechanisms depending on the severity of hypoxia. During physiologically relevant moderate hypoxia ( pO
2
~40 mmHg), glomus cells use heme oxygenase-2 (HO-2)/carbon monoxide (CO)/cystathionine-γ-lyase (CSE)/hydrogen sulfide (H
2
S) signaling pathway to stimulate CSN activity and breathing response to hypoxia. Basal CO restrains CSN activity during normoxia, whereas hypoxia reduces CO and stimulates CSN activity through H
2
S. Olfactory receptor 78 (Olfr78) is required for H
2
S-mediated CSN activation. CO-H
2
S pathway contributes to cardiorespiratory physiological adaptations to sustained hypoxia and to the pathophysiology of diseases characterized by carotid body (CB) hyperactivity. In contrast, glomus cell responds to severe hypoxia ( pO
2
~5–15 mmHg) through mitochondrial complex I (NDUFS2) and complex III. Thus, CBs appear to employ severity-dependent hypoxic sensing mechanisms wherein moderate hypoxia engages the CO–H
2
S pathway to activate CSN activity and drive homeostatic cardiorespiratory responses. Severe hypoxia primarily alters mitochondrial function and glomus cell metabolism. Physiological relevance of severe-hypoxia remains uncertain, because severe low O
2
levels suppresses both CB, CSN activity and ventilation.