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 (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.
Sattler
R
R
Toronto Western Hospital, University of Toronto, Lab 11-416, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
Xiong
Z
Z
Lu
W Y
WY
Hafner
M
M
MacDonald
J F
JF
Tymianski
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D004789:Enzyme Activation; D051528:Guanylate Kinases; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051379:Mice; D016202:N-Methylaspartate / Q000633:toxicity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D009703:Nucleoside-Phosphate Kinase / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction
D015220:Calcium Channels; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D016194:Receptors, N-Methyl-D-Aspartate; C033652:postsynaptic density proteins; D009569:Nitric Oxide; D016202:N-Methylaspartate; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; D002118:Calcium