Attenuation of NMDA receptor activity and neurotoxicity by nitroxyl anion, NO-.
Recent evidence indicates that the NO-related species, nitroxyl anion (NO), is produced in physiological systems by several redox metal-containing proteins, including hemoglobin, nitric oxide synthase (NOS), superoxide dismutase, and S-nitrosothiols (SNOs), which have recently been identified in brain. However, the chemical biology of NO- remains largely unknown. Here, we show that NO- -unlike NO*, but reminiscent of NO+ transfer (or S-nitrosylation)- -reacts mainly with Cys-399 in the NR2A subunit of the N-methyl-D-aspartate (NMDA) receptor to curtail excessive Ca2+ influx and thus provide neuroprotection from excitotoxic insults. This effect of NO- closely resembles that of NOS, which also downregulates NMDA receptor activity under similar conditions in culture.
Kim
W K
WK
Cerebrovascular and NeuroScience Research Institute, Brigham and Women's Hospital and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.
Choi
Y B
YB
Rayudu
P V
PV
Das
P
P
Asaad
W
W
Arnelle
D R
DR
Stamler
J S
JS
Lipton
S A
SA
D000818:Animals; D000838:Anions / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005260:Female; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D009498:Neurotoxins / Q000378:metabolism*; D009569:Nitric Oxide / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism*; D009865:Oocytes; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism; D014982:Xenopus laevis
D000838:Anions; D009498:Neurotoxins; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D016194:Receptors, N-Methyl-D-Aspartate; D013438:Sulfhydryl Compounds; D009569:Nitric Oxide; D016202:N-Methylaspartate; D019001:Nitric Oxide Synthase; C039900:nitroxyl