Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation

Several ion channels are thought to be directly modulated by nitric-oxide ( NO), but the molecular basis of this regulation is unclear. Here we show th at the NMDA receptor (NMDAR)-associated ion channel was modulated not only by exogenous NO but also by endogenous NO. Site-directed mutagenesis identi fied a critical cysteine residue (Cys 399) on the NR2A subunit whose S-nitr osylation (NO+ transfer) under physiological conditions underlies this modu lation. In cell systems expressing NMDARs with mutant NR2A subunits in whic h this single cysteine was replaced by an alanine, the effect of endogenous NO was lost. Thus endogenous S-nitrosylation can regulate ion channel acti vity.