S -Nitrosothiols signal the ventilatory response to hypoxia

Increased ventilation in response to hypoxia has been appreciated for over a century, but the biochemistry underlying this response remains poorly understood. Here we define a pathway in which increased minute ventilation ( E ) is signalled by deoxyhaemoglobin-derived S-nitrosothiols (SNOs). Specifi...

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Bibliographic Details
Published in:Nature (London) 2001-09, Vol.413 (6852), p.171-174
Main Authors: Gaston, Benjamin, Lipton, Andrew J, Johnson, Michael A, Macdonald, Timothy, Lieberman, Michael W, Gozal, David
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Biological and medical sciences
Cardiorespiratory control. Arterial mecano- and chemoreceptor
Cell Hypoxia
Cysteine - analogs & derivatives
Cysteine - metabolism
Fundamental and applied biological sciences. Psychology
gamma-Glutamyltransferase - antagonists & inhibitors
gamma-Glutamyltransferase - metabolism
Glutathione - analogs & derivatives
Glutathione - metabolism
Humanities and Social Sciences
Hypoxia
Isoxazoles - pharmacology
letter
Mice
multidisciplinary
Nitroso Compounds - metabolism
Oxygen - blood
Plasma
Rats
Respiratory Physiological Phenomena
Respiratory system
Rodents
S-Nitrosoglutathione
S-Nitrosothiols
Science
Science (multidisciplinary)
Solitary Nucleus - metabolism
Sulfhydryl Compounds - metabolism
Ventilation
Vertebrates: respiratory system
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Summary:Increased ventilation in response to hypoxia has been appreciated for over a century, but the biochemistry underlying this response remains poorly understood. Here we define a pathway in which increased minute ventilation ( E ) is signalled by deoxyhaemoglobin-derived S-nitrosothiols (SNOs). Specifically, we demonstrate that S-nitrosocysteinyl glycine (CGSNO) and S-nitroso-l-cysteine (l-CSNO)-but not S-nitroso-d-cysteine (d-CSNO)-reproduce the ventilatory effects of hypoxia at the level of the nucleus tractus solitarius (NTS). We show that plasma from deoxygenated, but not from oxygenated, blood produces the ventilatory effect of both SNOs and hypoxia. Further, this activity is mediated by S-nitrosoglutathione (GSNO), and GSNO activation by γ-glutamyl transpeptidase (γ-GT) is required. The normal response to hypoxia is impaired in a knockout mouse lacking γ-GT. These observations suggest that S-nitrosothiol biochemistry is of central importance to the regulation of breathing.
ISSN:0028-0836
1476-4687
DOI:10.1038/35093117