Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex.
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.
Lei
S Z
SZ
Department of Neurology, Children's Hospital, Boston, Massachusetts.
Pan
Z H
ZH
Aggarwal
S K
SK
Chen
H S
HS
Hartman
J
J
Sucher
N J
NJ
Lipton
S A
SA
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*
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