Abstract
Nitric oxide (NO)-related species include different redox states of the NO group, which have recently been reported to exist endogenously in biological tissues including the brain. The importance of these different NO-related species is that their distinct chemical reactivities can influence the life and death of neurons in response to various insults. In the case of NO+ equivalents (having one less electron than NO.), the mechanism of reaction often involves S-nitrosylation or transfer of the NO group to the sulfhydryl of a cysteine residue (or more properly to a thiolate anion) to form an RS-NO; further oxidation of critical thiols can possibly then form disulfide bonds from neighboring cysteine residues. We have mounted both physiological and chemical evidence that N-methyl-D-aspartate receptor (NMDAR) activity and caspase enzyme activity can be decreased by S-nitrosylation, as can other signaling molecules involved in neuronal apoptotic pathways, to afford neuroprotection. Over the past 5 years, beginning with our report on the NMDAR, evidence has accumulated that S-nitrosylation can regulate the biological activity of a great variety of proteins, in some ways akin to phosphorylation. Thus, this chemical reaction is gaining acceptance as a newly-recognized molecular switch to control protein function via reactive thiol groups, such as those encountered on the NMDAR and in the active site of caspases. One method of producing S-nitrosylation of the NMDAR and caspases is the administration of nitroglycerin, and nitroglycerin can be neuroprotective in acute focal ischemia/reperfusion models via mechanisms other than increasing cerebral blood flow. In contrast, NO. itself does not appear to react with thiol under physiological conditions. In fact, the favored reaction of NO. is with O2.− (superoxide anion) to form ONOO− (peroxynitrite), which can lead to neurotoxicity. A third NO-related species with one added electron compared to NO. is nitroxyl anion (NO−). NO− – unlike NO. but reminiscent of NO+ transfer–reacts with critical thiol groups of the NMDA receptor to curtail excessive Ca2+ influx and thus provide neuroprotection from excitotoxic insults.
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Lipton, S. Neuronal protection and destruction by NO. Cell Death Differ 6, 943–951 (1999). https://doi.org/10.1038/sj.cdd.4400580
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DOI: https://doi.org/10.1038/sj.cdd.4400580
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