Protein kinase G–regulated production of H ₂ S governs oxygen sensing

Abstract

Reflexes initiated by the carotid body, the principal O2-sensing organ, are critical for maintaining cardio-respiratory homeostasis during hypoxia. O2 sensing by the carotid body requires carbon monoxide (CO) generation by heme oxygenase-2 (HO-2) and hydrogen sulfide (H2S) synthesis by cystathionine-γ-lyase (CSE). We report that O2 stimulated the generation of CO, but not that of H2S, and required two cysteine residues in the heme regulatory motif (Cys265 and Cys282) of HO-2. CO stimulated protein kinase G (PKG)–dependent phosphorylation of Ser377 of CSE, inhibiting the production of H2S. Hypoxia decreased the inhibition of CSE by reducing CO generation resulting in increased H2S, which stimulated carotid body neural activity. In carotid bodies from mice lacking HO-2, compensatory increased abundance of nNOS (neuronal nitric oxide synthase) mediated O2 sensing through PKG-dependent regulation of H2S by nitric oxide. These results provide a mechanism for how three gases work in concert in the carotid body to regulate breathing.

Heme Oxygenase-1 in Kidney Health and Disease

“…These HRMs are independent of the enzymatic active site and bind heme with higher affinity (87). Yuan et al recently substantiated the role of HO-2 and HRMs in redox signaling and demonstrated a role in control of respiratory rate (152). Biochemical and structural NMR studies further supported the conclusion that HRMs in HO-2 allow cellular sensing and response to redox changes (12,42).…”

Regulation of carotid body oxygen sensing by hypoxia-inducible factors

“…While ROS resulting from imbalanced expression of HIF-α isoforms mediate the carotid body response to hypoxia, the downstream targets of ROS signaling have not yet been identified. Recent studies implicate carbon monoxide (CO)-sensitive hydrogen sulfide (H 2 S) generation as critical mediators of the carotid body response to hypoxia [18, 38]. Whether altered ROS levels result from dysregulated HIF-α isoform expression target CO and H 2 S signaling in the carotid body remains to be studied.…”

Carotid body chemoreflex: a driver of autonomic abnormalities in sleep apnoea

“…O 2 is a potent regulator of CO production from HO-2. Under normoxia, CO production is high whereas CO production is markedly decreased during hypoxia in the carotid body (Peng et al , 2010; Peng et al , 2014a; Yuan et al , 2015). The reduced CO generation, in turn activates CSE-dependent H 2 S synthesis through inhibition of protein kinase G-dependent phosphorylation of CSE (Yuan et al , 2015).…”