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• W2333130593 abstract "Editorial FocusH2S, a gasotransmitter for oxygen sensing in carotid body. Focus on “Endogenous H2S is required for hypoxic sensing by carotid body glomus cells”Kimberly A. Smith, and Jason X.-J. YuanKimberly A. SmithSection of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, Illinois, and Jason X.-J. YuanSection of Pulmonary, Critical Care, Sleep and Allergy, Department of Medicine, University of Illinois at Chicago, Chicago, Illinois; Institute for Personalized Respiratory Medicine, University of Illinois at Chicago, Chicago, Illinois; Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois; and Center for Cardiovascular Research, University of Illinois at Chicago, Chicago, IllinoisPublished Online:01 Nov 2012https://doi.org/10.1152/ajpcell.00307.2012This is the final version - click for previous versionMoreSectionsPDF (228 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat many, if not all, tissues possess the ability to sense hypoxia, and most tissues respond to hypoxia by reducing energy expenditure as a form of self-preservation. The carotid body, however, rapidly responds to hypoxic conditions by initiating cardiorespiratory reflexes in order to increase ventilation and systemic delivery of oxygen rather than initiating mechanisms for local conservation. The carotid body is made up of two types of cells, neuron-like glomus (type 1 cells) and glia-like sustentacular (type II) cells. The glomus cells were identified as the chemoreceptive component of the carotid body nearly 40 years ago in a seminal study by Verna and colleagues (8). Since then, much of the research on the carotid body has been devoted to understanding how glomus cells sense hypoxia and identifying the molecular components of this process.Following the identification of oxygen-sensitive K+ channels in glomus cells (3), a model of carotid body responsiveness termed the “membrane hypothesis” was developed. Briefly, hypoxia leads to inhibition of K+ channels, causing membrane depolarization, opening of voltage-dependent Ca2+ channels (VDCC), increasing cytosolic Ca2+ concentration ([Ca2+]cyt), and triggering the release of neurotransmitters (7, 8) (Fig. 1). While findings from most research groups agree with the basic process, there is some debate in the field as to the cascade of events leading to the inhibition of K+ channels, specifically the identity of the “oxygen sensor.”Fig. 1.Proposed mechanisms for hypoxia-mediated increase in sensory activity via H2S. Under normoxic conditions, cystathionine-γ-lyase (CSE) is inhibited by carbon monoxide (CO) produced via heme oxygenase-2 (HO-2). Hypoxia increases H2S in glomus cells due to increased activity of CSE as a result of decreased CO. Increased H2S may directly activate voltage-dependent Ca2+ channels (VDCC) or indirectly activate VDCC by causing membrane depolarization via the decrease in the large-conductance Ca2+-activated K+ (BKCa) channel activity. Since CO activates BKCa channels, decreased CO would lead to decreased BKCa channel activity and membrane depolarization. Activation of VDCC raises cytosolic Ca2+ concentration ([Ca2+]cyt) in the glomus cells and increases the sensory activity. In addition, hypoxia-mediated mitochondrial production of reactive oxygen species (ROS) has been shown to mobilize Ca2+ from the endoplasmic reticulum (ER), which not only increases [Ca2+]cyt but also activates the Ca2+-activated Cl− (ClCa) channels and causes further membrane depolarization. The hypoxia-mediated increases in H2S and ROS may work synergistically to induce membrane depolarization, increase [Ca2+]cyt, and eventually enhance the sensory activity.Download figureDownload PowerPointIn the current issue of American Journal of Physiology-Cell Physiology, Makarenko and colleagues (4) demonstrate that endogenous H2S is required for hypoxic sensing by glomus cells. H2S was first labeled a gasotransmitter in 2002 and has been demonstrated to be an important signaling molecule involved in a wide variety of biological effects (9). The majority of H2S in mammalian tissues is produced by two enzymes, cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) (9). Previous studies have demonstrated a role for H2S in response to hypoxia, and the authors of the current study recently showed that genetic deletion of CSE is sufficient to disrupt the hypoxic response in the carotid body (2, 5, 6). In the current study, Makarenko et al. demonstrate that the glomus cells are the site for H2S-dependent oxygen sensing in the carotid body (4). The authors demonstrate that the CSE is present in glomus cells and that inhibition of CSE in glomus cells blocks the hypoxia-induced increase in H2S levels. Inhibition of CSE, either pharmacologically or genetically, also blocks hypoxia-induced secretion of catecholamine, but not high K+-induced catecholamine secretion in glomus cells. Hypoxia induces an increase in [Ca2+]cyt which the authors show can be mimicked by addition of an H2S donor and which is attenuated in CSE−/− glomus cells, demonstrating a role for H2S in hypoxia-induced rise in [Ca2+]cyt through L-type VDCC. Indeed, the broad spectrum VDCC blocker, Cd2+, and the L-type VDCC specific blocker, nifedipine, both blocked the hypoxia- and H2S-induced increase in [Ca2+]cyt.The authors propose that H2S generated by CSE mediates the hypoxic response of glomus cells in the following manner: Under normoxic conditions, hemeoxygenase-2 (HO-2) converts heme to carbon monoxide (CO), biliverdin, and Fe2+. Previous studies demonstrated that CO generated by HO-2 tonically activates the large-conductance Ca2+-activated K+ (BKCa) channels (10) and other types of K+ channels. CO also suppresses H2S production by inhibition of CSE. Hypoxia diminishes HO-2 production of CO, resulting in increased H2S which can inhibit BKCa channels (2). This leads to membrane depolarization, opening of L-type Ca2+ channels, and increased sensory activity (Fig. 1).Multiple mechanisms have been proposed to mediate oxygen sensing in the carotid body [such as HO-2/CO, AMP-activated protein kinase (AMPK), and mitochondrial reactive oxygen species (ROS)], with evidence presented to support each theory (1, 10). Given that the cardiorespiratory response to hypoxia is essential for survival, it seems possible that a combination of these theories may be involved in oxygen sensing by the carotid body (Fig. 1). The current study by Makarenko et al. provides compelling evidence that H2S in glomus cells is another critical gasotransmitter required in oxygen sensing in carotid body.Further studies are needed to define 1) whether H2S directly opens VDCC and, if so, which type of VDCC (e.g., L-, T-, N-, R-, and/or P/Q-type) is directly activated and which transmembrane domain and extracellular or intracellular loop of the channel are affected by H2S; 2) whether H2S, in addition to directly activating BKCa channels, inhibits other types of K+ channels (e.g., the intermediate- and small-conductance Ca2+-activated K+ channels, voltage-gated K+ channels, two-pore domain K+ channels, and/or inward-rectifier K+ channels) and regulates other cation (e.g., Na+- or Ca2+-permeable) and anion (e.g., Cl−-permeable) channels in glomus cells; 3) whether H2S synergistically regulates the channel activity with other oxygen-sensing molecules or gasotransmitters, such as CO and nitric oxide; and 4) whether H2S-mediated effect on [Ca2+]cyt in glomus cells is sensitive to the cellular redox status. The oxygen sensing in the carotid type I glomus cells must be a complicated process which may require precise coordination of many different sensors, receptors, and effectors.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).AUTHOR CONTRIBUTIONSK.A.S. and J.X.-J.Y. prepared the figure; drafted the manuscript; edited and revised the manuscript; approved the final version of the manuscript.REFERENCES1. Chandel NS, Schumacker PT. Cellular oxygen sensing by mitochondria: old questions, new insight. J Appl Physiol 88: 1880–1889, 2000.Link | ISI | Google Scholar2. Li Q, Sun B, Wang X, Jin Z, Zhou Y, Dong L, Jiang LH, Rong W. A crucial role for hydrogen sulfide in oxygen sensing via modulating large conductance calcium-activated potassium channels. Antioxid Redox Signal 12: 1179–1189, 2010.Crossref | PubMed | ISI | Google Scholar3. Lopez-Barneo J, Lopez-Lopez JR, Urena J, Gonzalez C. Chemotransduction in the carotid body: K+ current modulated by Po2 in type I chemoreceptor cells. Science 241: 580–582, 1988.Crossref | PubMed | ISI | Google Scholar4. Makarenko VV, Nanduri J, Raghuraman G, Fox AP, Gadalla MM, Kumar GK, Snyder SH, Prabhakar NR. Endogenous H2S is required for hypoxic sensing by carotid body glomus cells. Am J Physiol Cell Physiol (June 27, 2012). doi:10.1152/ajpcell.00100.2012.Google Scholar5. Olson KR, Dombkowski RA, Russell MJ, Doellman MM, Head SK, Whitfield NL, Madden JA. Hydrogen sulfide as an oxygen sensor/transducer in vertebrate hypoxic vasoconstriction and hypoxic vasodilation. J Exp Biol 209: 4011–4023, 2006.Crossref | PubMed | ISI | Google Scholar6. Peng YJ, Nanduri J, Raghuraman G, Souvannakitti D, Gadalla MM, Kumar GK, Snyder SH, Prabhakar NR. H2S mediates O2 sensing in the carotid body. Proc Natl Acad Sci USA 107: 10719–10724, 2010.Crossref | PubMed | ISI | Google Scholar7. Urena J, Fernandez-Chacon R, Benot AR, Alvarez de Toledo GA, Lopez-Barneo J. Hypoxia induces voltage-dependent Ca2+ entry and quantal dopamine secretion in carotid body glomus cells. Proc Natl Acad Sci USA 91: 10208–10211, 1994.Crossref | PubMed | ISI | Google Scholar8. Verna A, Roumy M, Leitner LM. Loss of chemoreceptive properties of the rabbit carotid body after destruction of the glomus cells. Brain Res 100: 13–23, 1975.Crossref | PubMed | ISI | Google Scholar9. Wang R. Two's company, three's a crowd: can H2S be the third endogenous gaseous transmitter? FASEB J 16: 1792–1798, 2002.Crossref | PubMed | ISI | Google Scholar10. Williams SE, Wootton P, Mason HS, Bould J, Iles DE, Riccardi D, Peers C, Kemp PJ. Hemoxygenase-2 is an oxygen sensor for a calcium-sensitive potassium channel. Science 306: 2093–2097, 2004.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: J. X.-J. Yuan, Dept. of Medicine, Univ. of Illinois at Chicago, COMRB 3131, MC 719, 909 South Wolcott Ave., Chicago, IL 60612 (e-mail: jxyuan@uic.edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByPhysiological roles of hydrogen sulfide in mammalian cells, tissues, and organsGiuseppe Cirino,* Csaba Szabo,* and Andreas Papapetropoulos*12 October 2022 | Physiological Reviews, Vol. 103, No. 1Hydrogen sulfide activates TRPA1 and releases 5-HT from epithelioid cells of the chicken thoracic aortaComparative Biochemistry and Physiology Part C: Toxicology & Pharmacology, Vol. 187Regulation of mitochondrial bioenergetic function by hydrogen sulfide. Part I . Biochemical and physiological mechanisms28 March 2014 | British Journal of Pharmacology, Vol. 171, No. 8 More from this issue > Volume 303Issue 9November 2012Pages C911-C912 Copyright & PermissionsCopyright © 2012 the American Physiological Societyhttps://doi.org/10.1152/ajpcell.00307.2012PubMed22992680History Published online 1 November 2012 Published in print 1 November 2012 Metrics" @default.
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