Signal Transduction Pathway Mediating Carotid Body Dependent Sympathetic Activation and Hypertension by Chronic Intermittent Hypoxia

Patients with obstructive sleep apnea (OSA) experience chronic intermittent hypoxia (CIH). OSA patients and CIH-treated rodents exhibit overactive sympathetic nervous system and hypertension, mediated through hyperactive carotid body (CB) chemoreflex. Activation of olfactory receptor 78 (Olfr78) by hydrogen sulfide (H2S) is implicated in CB activation and sympathetic nerve 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 sympathetic responses to CIH. Our findings show that CIH increases cAMP levels in the CB, a response absent in Adcy3, Cth (encoding CSE), and Olfr78 null mice. CBs from Cth and Olfr78 mutant mice lacked persulfidation response to CIH, indicating that Adcy3 activation requires Olfr78 activation by H2S in CIH. CIH also enhanced glomus cell Ca2+ influx, an effect absent in Cnga2 (encoding cyclic nucleotide gated channel alpha2 subunit) and Adcy3 mutants, suggesting that CIH-induced cAMP mediates enhanced Ca2+ responses through cyclic nucleotide-gated channels. Furthermore, Adcy3 null mice did not exhibit neither CB activation nor sympathetic activation by CIH. These results demonstrate that Adcy3-dependent cAMP is a downstream signaling pathway to H2S/Olfr78, mediating CIH-induced CB activation and sympathetic activity and hypertension. NEW & NOTEWORTHY: The current study demonstrates that chronic intermittent hypoxia patterned after blood O2 levels during sleep apnea activates adenylate cyclase 3 in the carotid body involving olfactory receptor 78 (Olfr78) activation by H2S through persulfidation. The ensuing hyperactive carotid body chemoreflex activates sympathetic nervous system leading to hypertension.