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Protein kinase G-regulated production of H2S governs oxygen sensing.
Sci Signal. 2015 Apr 21; 8(373):ra37.SS

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.

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Authors+Show Affiliations

Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.

Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.

Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.

Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.

Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.

Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.

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.

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.

Institute for Integrative Physiology and Center for Systems Biology for O2 Sensing, Biological Sciences Division, University of Chicago, Chicago, IL 60637, USA.

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.

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.

Pub Type(s)

Journal Article

Research Support, N.I.H., Extramural

Language

eng

PubMed ID

25900831

Citation

Yuan, Guoxiang, et al. "Protein Kinase G-regulated Production of H2S Governs Oxygen Sensing." Science Signaling, vol. 8, no. 373, 2015, pp. ra37.

Yuan G, Vasavda C, Peng YJ, et al. Protein kinase G-regulated production of H2S governs oxygen sensing. Sci Signal. 2015;8(373):ra37.

Yuan, G., Vasavda, C., Peng, Y. J., Makarenko, V. V., Raghuraman, G., Nanduri, J., Gadalla, M. M., Semenza, G. L., Kumar, G. K., Snyder, S. H., & Prabhakar, N. R. (2015). Protein kinase G-regulated production of H2S governs oxygen sensing. Science Signaling, 8(373), ra37. https://doi.org/10.1126/scisignal.2005846

Yuan G, et al. Protein Kinase G-regulated Production of H2S Governs Oxygen Sensing. Sci Signal. 2015 Apr 21;8(373):ra37. PubMed PMID: 25900831.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Protein kinase G-regulated production of H2S governs oxygen sensing. AU - Yuan,Guoxiang, AU - Vasavda,Chirag, AU - Peng,Ying-Jie, AU - Makarenko,Vladislav V, AU - Raghuraman,Gayatri, AU - Nanduri,Jayasri, AU - Gadalla,Moataz M, AU - Semenza,Gregg L, AU - Kumar,Ganesh K, AU - Snyder,Solomon H, AU - Prabhakar,Nanduri R, Y1 - 2015/04/21/ PY - 2015/4/23/entrez PY - 2015/4/23/pubmed PY - 2016/1/21/medline SP - ra37 EP - ra37 JF - Science signaling JO - Sci Signal VL - 8 IS - 373 N2 - 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. SN - 1937-9145 UR - https://www.unboundmedicine.com/medline/citation/25900831/Protein_kinase_G_regulated_production_of_H2S_governs_oxygen_sensing_ DB - PRIME DP - Unbound Medicine ER -