Title

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

Document Type

Article

Abstract

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 (Ca2+) channels. NMDAR function was unaffected, because receptor expression, NMDA currents, and 45Ca2+ loading were unchanged. Suppressing PSD-95 blocked Ca2+- 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 Ca2+ signaling.

Publication Date

6-11-1999

Publication Title

Science

ISSN

00368075

Volume

284

Issue

5421

First Page

1845

Last Page

1848

PubMed ID

10364559

Digital Object Identifier (DOI)

10.1126/science.284.5421.1845

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