Nitric oxide: role in neurotoxicity.
1. Nitric oxide (NO) is a novel neuronal messenger molecule which interacts with surrounding neurones, not by synaptic transmission but by diffusion between cells. 2. NO is produced following stimulation of the enzyme, NO synthase (NOS). After synthesis, NO exerts its biological actions by diffusion to the site of action. Therefore, the way to regulate the physiological actions of NO is to regulate NOS. 3. NOS is activated by the influx of calcium from glutamate-activated N-methyl-D-aspartate receptors. Overactivation of these receptors leads to overproduction of NO and neuronal cell death. 4. NOS can be regulated at the catalytic site, at the flavo-proteins, at the calmodulin site and by phosphorylation. 5. In excess, NO is toxic to neurones. This toxicity is mediated largely by an interaction with the superoxide anion, presumably through the generation of the oxidant, peroxynitrite. 6. NO or peroxynitrite-mediated neuronal injury involves the activation of the nuclear protein, poly(ADP-ribose)synthetase.
Dawson
V L
VL
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
D000594:Amino Acid Oxidoreductases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D004249:DNA Damage; D004058:Diffusion; D004789:Enzyme Activation / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009566:Nitrates / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000378:metabolism / Q000633:toxicity; D019001:Nitric Oxide Synthase; D010766:Phosphorylation; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D002148:Calmodulin-Binding Proteins; D009566:Nitrates; D016194:Receptors, N-Methyl-D-Aspartate; D013481:Superoxides; C039642:peroxynitric acid; D009569:Nitric Oxide; D018698:Glutamic Acid; D019001:Nitric Oxide Synthase; D000594:Amino Acid Oxidoreductases; D011065:Poly(ADP-ribose) Polymerases; D002118:Calcium