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 types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcium / metabolism*
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Calcium Channels / metabolism
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Cell Survival
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Cells, Cultured
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Disks Large Homolog 4 Protein
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Enzyme Activation
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Guanylate Kinases
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Mice
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N-Methylaspartate / toxicity
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neurons / cytology
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Neurons / metabolism*
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Nitric Oxide / metabolism*
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Nitric Oxide Synthase / metabolism
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Nitric Oxide Synthase Type I
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Nucleoside-Phosphate Kinase / metabolism
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Oligodeoxyribonucleotides, Antisense
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Patch-Clamp Techniques
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Second Messenger Systems
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Signal Transduction
Substances
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Calcium Channels
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Nerve Tissue Proteins
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Oligodeoxyribonucleotides, Antisense
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Receptors, N-Methyl-D-Aspartate
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postsynaptic density proteins
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Nitric Oxide
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N-Methylaspartate
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type I
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Nos1 protein, mouse
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Nucleoside-Phosphate Kinase
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Guanylate Kinases
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Calcium