Redox modulation of the NMDA receptor

Redox modulation has been recognized to be an important mechanism of regula tion for the N-methyl-D-aspartate (NMDA) receptor. Sulfhydryl reducing agen ts enhance, whereas oxidizing agents decrease, NMDA-evoked currents. Multip le cysteine residues located in different NMDA receptor subunits have been identified as molecular determinants underlying redox modulation. The NMDA receptor is also regulated by nitric oxide (NO)-related species directly, n ot involving cyclic GMP, but the molecular mechanism of this action has her etofore not been entirely clear. The confusion arose at least partly due to the fact that various redox forms of NO (NO+, NO., NO-, each having an add itional electron compared with the previous) have distinct mechanisms of ac tion. Recently, a critical cysteine residue (Cys 399) on the NR2A subunit h as been shown to react under physiological conditions with NO by S-nitrosyl ation (transfer of the NO+ to cysteine thiol) or by reaction with NO- (nitr oxyl anion) to underlie this form of modulation.