title: Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex.
abstract: Nitric oxide (NO) is an important messenger both systemically and in the CNS. In digital Ca2+ imaging and patch-clamp experiments, clinically available nitroso compounds that generate NO are shown to inhibit responses mediated by the NMDA subtype of the glutamate receptor on rat cortical neurons in vitro. A mechanism of action for this effect was investigated by using the specific NO-generating agent S-nitrosocysteine. We propose that free sulfhydryl groups on the NMDA receptor-channel complex react to form one or more S-nitrosothiols in the presence of NO. If vicinal thiol groups react in this manner, they can form a disulfide bond(s), which is thought to constitute the redox modulatory site of the receptor, resulting in a relatively persistent blockade of NMDA responses. These reactions with NO can afford protection from NMDA receptor-mediated neurotoxicity. Our results demonstrate a new pathway for NO regulation of physiological function that is not via cGMP, but instead involves reactions with membrane-bound thiol groups on the NMDA receptor-channel complex.
authors.affiliation: Department of Neurology, Children's Hospital, Boston, Massachusetts.
authors.forename: S Z
authors.initials: SZ
authors.lastname: Lei
authors.forename: Z H
authors.initials: ZH
authors.lastname: Pan
authors.forename: S K
authors.initials: SK
authors.lastname: Aggarwal
authors.forename: H S
authors.initials: HS
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Hartman
authors.forename: N J
authors.initials: NJ
authors.lastname: Sucher
authors.forename: S A
authors.initials: SA
authors.lastname: Lipton
mesh_terms: D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004594:Electrophysiology; D007425:Intracellular Membranes / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D009603:Nitroso Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D011188:Potassium / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D000477:Alkylating Agents; D007473:Ion Channels; D009603:Nitroso Compounds; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D016202:N-Methylaspartate; D011188:Potassium; D007608:Kainic Acid; D002118:Calcium