title: Protein kinase G-regulated production of H2S governs oxygen sensing.
abstract: Reflexes initiated by the carotid body, the principal O2-sensing organ, are critical for maintaining cardiorespiratory 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 (Cys(265) and Cys(282)) of HO-2. CO stimulated protein kinase G (PKG)-dependent phosphorylation of Ser(377) 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.
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Yuan
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Chirag
authors.initials: C
authors.lastname: Vasavda
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ying-Jie
authors.initials: YJ
authors.lastname: Peng
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Makarenko
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Gayatri
authors.initials: G
authors.lastname: Raghuraman
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Jayasri
authors.initials: J
authors.lastname: Nanduri
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Moataz M
authors.initials: MM
authors.lastname: Gadalla
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry; and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Gregg L
authors.initials: GL
authors.lastname: Semenza
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Ganesh K
authors.initials: GK
authors.lastname: Kumar
authors.affiliation: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
authors.affiliation: Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA. nanduri@uchicago.edu.
authors.forename: Nanduri R
authors.initials: NR
authors.lastname: Prabhakar
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D002118:Calcium / Q000737:chemistry; D002344:Carotid Body / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D003542:Cystathionine gamma-Lyase / Q000378:metabolism; D003545:Cysteine / Q000737:chemistry; D005260:Female; D005740:Gases; D057809:HEK293 Cells; D006418:Heme / Q000737:chemistry; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006801:Humans; D006862:Hydrogen Sulfide / Q000737:chemistry*; D000860:Hypoxia; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010100:Oxygen / Q000737:chemistry*; D010766:Phosphorylation; D020033:Protein Isoforms / Q000378:metabolism; D012119:Respiration
chemical_list: D005740:Gases; D020033:Protein Isoforms; D006418:Heme; D006419:Heme Oxygenase (Decyclizing); C105245:heme oxygenase-2; D017869:Cyclic GMP-Dependent Protein Kinases; D003542:Cystathionine gamma-Lyase; D003545:Cysteine; D010100:Oxygen; D002118:Calcium; D006862:Hydrogen Sulfide