Nitric Oxide NO, Not O₂, Controls Breathing

Nitric oxide is a highly reactive gas, which has been implicated in many signaling pathways through its ability to regulate protein function by S-nitrosylation (see the Review by Lane et al.). Lipton et al. provide evidence that S-nitrosothiols, specifically S-nitrosocysteinyl glycine (CGSNO) and S-nitroso-L-cysteine (L-CSNO), stimulate minute ventilation (a measure of respiration) in conscious rats, mimicking the effects of hypoxia in the nucleus tractus solitarii (the site of respiratory regulation in the brain). In deoxygenated blood, S-nitrosothiols appear to be transferred from hemoglobin to glutathione, forming S-nitrosoglutathione (GSNO) from which the active S-nitrosothiols are produced by cleavage with the enzyme -glutamyl transpeptidase. The production of the active S-nitrosothiols and the increase in ventilation produced by microinjection of GSNO into the nucleus tractus solitarii was inhibited by treatment of the nucleus tractus solitarii with the -glutamyl transpeptidase inhibitor acivicin. The importance of -glutamyl transpeptidase in mediating the hypoxic response in ventilation was confirmed in mice deficient for the gene; such mice did not increase respiration in response to hypoxia. A discussion of how these findings extend the roles for nitric oxide in controlling oxygen delivery from regulating the airway diameter to blood vessel dilation to respiration rate is presented by Lipton.

P. Lane, G. Hao, S. S. Gross, S-Nitrosylation is emerging as a specific and fundamental posttranslational protein modification: Head-to-head comparison with O-phosphorylation. Science's STKE (2001), http://stke.sciencemag.org/cgi/content/full/OC_sigtrans;2001/86/re1. [Abstract] [Full Text]

A. J. Lipton, M. A. Johnson, T. Macdonald, M. W. Lieberman, D. Gozal, B. Gaston, S-Nitrosothiols signal the ventilatory response to hypoxia. Nature 413, 171-174 (2001). [Online Journal]

S. A. Lipton, Nitric oxide and respiration. Nature 413, 118-121 (2001). [Online Journal]