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.