S-nitrosylation/activation of COX-2 mediates NMDA neurotoxicity.
Glutamate/N-methyl-d-aspartate (NMDA) receptor-mediated neurotoxicity involves cyclooxygenase (COX)-2. We demonstrate that this neurotoxicity reflects activation of COX-2 by S-nitrosylation after selective binding of neuronal nitric oxide synthase (nNOS) to COX-2. nNOS, via its PDZ domain, binds COX-2 with the generated NO S-nitrosylating and activating the enzyme. Selective disruption of nNOS-COX-2 binding prevents NMDA neurotoxicity.
Tian
Jing
J
Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA.
Kim
Sangwon F
SF
Hester
Lynda
L
Snyder
Solomon H
SH
D000818:Animals; D001710:Biotin / Q000737:chemistry; D001921:Brain / Q000378:metabolism; D016923:Cell Death; D002531:Cerebellum / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D004789:Enzyme Activation; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity*; D009474:Neurons / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D011485:Protein Binding; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000378:metabolism
D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D001710:Biotin; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2