ADENYLATE CYCLASE 3 MEDIATES CAROTID BODY ACTIVATION AND AUTONOMIC DYSFUNCTION IN A SLEEP APNEA MODEL

Patients with obstructive sleep apnea (OSA) experience chronic intermittent hypoxia (CIH). OSA patients and CIH-treated rodents exhibit autonomic dysfunction, characterized by overactive sympathetic nervous system and hypertension, mediated through hyperactive carotid body (CB) chemoreflex. Activation of olfactory receptor 78 (Olfr78) by hydrogen sulfide (H ₂ S) is implicated in CB activation and autonomic responses to CIH, but the downstream signaling pathways remain unknown. Given that odorant receptor signaling is coupled to adenylyl cyclase 3 (Adcy3), we hypothesized that Adcy3-dependent cAMP contributes to CB and autonomic responses to CIH. Our findings show that CIH increases cAMP levels in the CB, a response absent in Adcy3 , Cth , and Olfr78 null mice. CBs from Cth and Olfr78 mutant mice lacked persulfidation response to CIH, indicating that Adcy3 activation by CIH requires Olfr78 activation by H ₂ S. CIH also enhanced glomus cell Ca ²⁺ influx, an effect absent in Cnga2 and Adcy3 mutants, suggesting that CIH-induced cAMP mediates enhanced Ca ²⁺ responses through cyclic nucleotide-gated channels. Furthermore, Adcy3 null mice did not exhibit neither CB activation nor autonomic dysfunction by CIH. These results demonstrate that Adcy3-dependent cAMP is a downstream signaling pathway to H ₂ S/Olfr78, mediating CIH-induced CB activation and autonomic dysfunction.