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 intracellular signaling pathways governs neuronal plasticity, development, senescence, and disease. In cultured cortical neurons, suppressing the expression of the NMDAR scaffolding protein PSD-95 (postsynaptic density–95) selectively attenuated excitotoxicity triggered via NMDARs, but not by other glutamate or calcium ion (Ca 2+ ) channels. NMDAR function was unaffected, because receptor expression, NMDA currents, and 45 Ca 2+ loading were unchanged. Suppressing PSD-95 blocked Ca 2+ -activated nitric oxide production by NMDARs selectively, without affecting neuronal nitric oxide synthase expression or function. Thus, PSD-95 is required for efficient coupling of NMDAR activity to nitric oxide toxicity, and imparts specificity to excitotoxic Ca 2+ signaling.