Role of nitric oxide-mediated glutathionylation in neuronal function: potential regulation of energy utilization.
Excessive generation of nitric oxide radical (NO*) in neuroinflammation, excitotoxicity and during age-related neurodegenerative disorders entails the localized and concerted increase in nitric oxide synthase(s) expression in glial cells and neurons. The aim of the present study was to assess the biological significance of the impact of NO* on the cell's thiol status with emphasis on S-glutathionylation of targeted proteins. Exposure of primary cortical neurons or astrocytes to increasing flow rates of NO* (0.061-0.25 microM/s) resulted in the following. (i) A decrease in GSH (glutathione) in neurons accompanied by formation of GSNO (S-nitrosoglutathione) and GSSG (glutathione disulfide); neurons were far more sensitive to NO* exposure than astrocytes. (ii) A dose-dependent oxidation of the cellular redox status: the neuron's redox potential increased approximately 42 mV and that of astrocytes approximately 23 mV. A good correlation was observed between cell viability and the cellular redox potential. The higher susceptibility of neurons to NO* can be partly explained by a reduced capacity to recover GSH through lower activities of GSNO and GSSG reductases. (iii) S-glutathionylation of a small subset of proteins, among them GAPDH (glyceraldehyde-3-phosphate dehydrogenase), the S-glutathionylation of which resulted in inhibition of enzyme activity. The quantitative analyses of changes in the cell's thiol potential upon NO* exposure and their consequences for S-glutathionylation are discussed in terms of the distinct redox environment of astrocytes and neurons.
Yap
Li-Peng
LP
Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA.
Garcia
Jerome V
JV
Han
Derick S
DS
Cadenas
Enrique
E
D000818:Animals; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D026422:S-Nitrosoglutathione / Q000378:metabolism
D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005978:Glutathione; D019803:Glutathione Disulfide