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Gaseous messengers in oxygen sensing.
J Mol Med (Berl). 2012 Mar; 90(3):265-72.JM

Abstract

The carotid body is a sensory organ that detects acute changes in arterial blood oxygen (O(2)) levels and reflexly mediates systemic cardiac, vascular, and respiratory responses to hypoxia. This article provides a brief update of the roles of gas messengers as well as redox homeostasis by hypoxia-inducible factors (HIFs) in hypoxic sensing by the carotid body. Carbon monoxide (CO) and nitric oxide (NO), generated by heme oxygenase-2 (HO-2) and neuronal nitric oxide synthase (nNOS), respectively, inhibit carotid body activity. Molecular O(2) is a required substrate for the enzymatic activities of HO-2 and nNOS. Stimulation of carotid body activity by hypoxia may reflect reduced formation of CO and NO. Glomus cells, the site of O(2) sensing in the carotid body, express cystathionine γ-lyase (CSE), an H(2)S generating enzyme. Cth (-/-) mice, which lack CSE, exhibit severely impaired hypoxia-induced H(2)S generation, sensory excitation, and stimulation of breathing in response to low O(2). Hypoxia-evoked H(2)S generation in the carotid body requires the interaction of CSE with HO-2, which generates CO. Carotid bodies from Hif1a (+/-) mice with partial HIF-1α deficiency do not respond to hypoxia, whereas carotid bodies from mice with partial HIF-2α deficiency are hyper-responsive to hypoxia. The opposing roles of HIF-1α and HIF-2α in the carotid body have provided novel insight into molecular mechanisms of redox homeostasis and its role in hypoxia sensing. Heightened carotid body activity has been implicated in the pathogenesis of autonomic morbidities associated with sleep-disordered breathing, congestive heart failure, and essential hypertension. The enzymes that generate gas messengers and redox regulation by HIFs represent potential therapeutic targets for normalizing carotid body function and downstream autonomic output in these disease states.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Prabhakar NR
Institute for Integrative Physiology and Center for Systems Biology of O2 Sensing, The University of Chicago, Chicago, IL 60637, USA. nanduri@uchicago.edu
Semenza GL
No affiliation info available

MeSH

AnimalsCarbon MonoxideCarotid BodyGasesHumansHydrogen SulfideHypoxiaMiceNitric OxideOxygenReactive Oxygen SpeciesSecond Messenger Systems

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

22349394

Citation

Prabhakar, Nanduri R., and Gregg L. Semenza. "Gaseous Messengers in Oxygen Sensing." Journal of Molecular Medicine (Berlin, Germany), vol. 90, no. 3, 2012, pp. 265-72.
Prabhakar NR, Semenza GL. Gaseous messengers in oxygen sensing. J Mol Med (Berl). 2012;90(3):265-72.
Prabhakar, N. R., & Semenza, G. L. (2012). Gaseous messengers in oxygen sensing. Journal of Molecular Medicine (Berlin, Germany), 90(3), 265-72. https://doi.org/10.1007/s00109-012-0876-1
Prabhakar NR, Semenza GL. Gaseous Messengers in Oxygen Sensing. J Mol Med (Berl). 2012;90(3):265-72. PubMed PMID: 22349394.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gaseous messengers in oxygen sensing. AU - Prabhakar,Nanduri R, AU - Semenza,Gregg L, Y1 - 2012/02/16/ PY - 2012/01/03/received PY - 2012/02/01/accepted PY - 2012/01/30/revised PY - 2012/2/22/entrez PY - 2012/2/22/pubmed PY - 2012/7/6/medline SP - 265 EP - 72 JF - Journal of molecular medicine (Berlin, Germany) JO - J Mol Med (Berl) VL - 90 IS - 3 N2 - The carotid body is a sensory organ that detects acute changes in arterial blood oxygen (O(2)) levels and reflexly mediates systemic cardiac, vascular, and respiratory responses to hypoxia. This article provides a brief update of the roles of gas messengers as well as redox homeostasis by hypoxia-inducible factors (HIFs) in hypoxic sensing by the carotid body. Carbon monoxide (CO) and nitric oxide (NO), generated by heme oxygenase-2 (HO-2) and neuronal nitric oxide synthase (nNOS), respectively, inhibit carotid body activity. Molecular O(2) is a required substrate for the enzymatic activities of HO-2 and nNOS. Stimulation of carotid body activity by hypoxia may reflect reduced formation of CO and NO. Glomus cells, the site of O(2) sensing in the carotid body, express cystathionine γ-lyase (CSE), an H(2)S generating enzyme. Cth (-/-) mice, which lack CSE, exhibit severely impaired hypoxia-induced H(2)S generation, sensory excitation, and stimulation of breathing in response to low O(2). Hypoxia-evoked H(2)S generation in the carotid body requires the interaction of CSE with HO-2, which generates CO. Carotid bodies from Hif1a (+/-) mice with partial HIF-1α deficiency do not respond to hypoxia, whereas carotid bodies from mice with partial HIF-2α deficiency are hyper-responsive to hypoxia. The opposing roles of HIF-1α and HIF-2α in the carotid body have provided novel insight into molecular mechanisms of redox homeostasis and its role in hypoxia sensing. Heightened carotid body activity has been implicated in the pathogenesis of autonomic morbidities associated with sleep-disordered breathing, congestive heart failure, and essential hypertension. The enzymes that generate gas messengers and redox regulation by HIFs represent potential therapeutic targets for normalizing carotid body function and downstream autonomic output in these disease states. SN - 1432-1440 UR - https://www.unboundmedicine.com/medline/citation/22349394/Gaseous_messengers_in_oxygen_sensing_ DB - PRIME DP - Unbound Medicine ER -