Hypoxia sensing requires H ₂ S-dependent persulfidation of olfactory receptor 78

Abstract

Oxygen (O 2 ) sensing by the carotid body is critical for maintaining cardiorespiratory homeostasis during hypoxia. Hydrogen sulfide (H 2 S) signaling is implicated in carotid body activation by low O 2 . Here, we show that persulfidation of olfactory receptor 78 (Olfr78) by H 2 S is an integral component of carotid body activation by hypoxia. Hypoxia and H 2 S increased persulfidation in carotid body glomus cells and persulfidated cysteine 240 in Olfr78 protein in heterologous system. Olfr78 mutants manifest impaired carotid body sensory nerve, glomus cell, and breathing responses to H 2 S and hypoxia. Glomus cells are positive for G Olf, adenylate cyclase 3 (Adcy3) and cyclic nucleotide–gated channel alpha 2 (Cnga2), key molecules of odorant receptor signaling. Adcy3 or Cnga2 mutants exhibited impaired carotid body and glomus cell responses to H 2 S and breathing responses to hypoxia. These results suggest that H 2 S through redox modification of Olfr78 participates in carotid body activation by hypoxia to regulate breathing.