Attenuation of NMDA Receptor Activity and Neurotoxicity by Nitroxyl Anion, NO

• Published in: Neuron (Cambridge, Mass.) Mass.), 1999-10, Vol.24 (2), p.461-469
• Main Authors: Kim, Won-Ki, Choi, Yun-Beom, Rayudu, Posina V., Das, Prajnan, Asaad, Wael, Arnelle, Derrick R., Stamler, Jonathan S., Lipton, Stuart A.
• Format: Article
• Language: English
• Subjects: Animals; Anions - metabolism; Cells, Cultured; Cerebral Cortex - cytology; Female; N-Methylaspartate - pharmacology; Neurons - metabolism; Neurotoxins - metabolism; Nitric Oxide - pharmacology; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase - metabolism; Nitrogen Oxides - metabolism; Oocytes; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate - chemistry; Receptors, N-Methyl-D-Aspartate - drug effects; Receptors, N-Methyl-D-Aspartate - metabolism; Receptors, N-Methyl-D-Aspartate - physiology; Sulfhydryl Compounds - chemistry; Sulfhydryl Compounds - metabolism; Xenopus laevis
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/S0896-6273(00)80859-4

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 Ca 2+ 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.