Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein

The efficiency with which N-methyl-D-aspartate receptors (NMDARs) trigger i ntracellular signaling pathways governs neuronal plasticity, development, s enescence, and disease. In cultured cortical neurons, suppressing the expre ssion of the NM DAR scaffolding protein PSD-95 (postsynaptic density-95) se lectively attenuated excitotoxicity triggered via NMDARs, but not by other glutamate or calcium ion (Ca2+) channels. NMDAR function was unaffected, be cause receptor expression, NMDA currents, and Ca-45(2+) loading were unchan ged. Suppressing PSD-95 blocked Ca2+-activated nitric oxide production by N MDARs selectively, without affecting neuronal nitric oxide synthase express ion or function. Thus, PSD-95 is required for efficient coupling of NMDAR a ctivity to nitric oxide toxicity, and imparts specificity to excitotoxic Ca 2+ signaling.