Abstract
In contrast to the rapid regulation of AMPA receptors, previous evidence has supported the idea that the synaptic density of NMDA-type glutamate receptors is fairly static, modulated only over a long time scale in a homeostatic manner. We report here that selective activation of protein kinase C (PKC) with phorbol esters induces a rapid dispersal of NMDA receptors from synaptic to extrasynaptic plasma membrane in cultured rat hippocampal neurons. PKC activation induced a simultaneous translocation of calcium/calmodulin-dependent kinase II (CaMKII) to synapses but no change in spine number, presynaptic terminal number, or the distribution of AMPA receptors or the synaptic scaffolding protein PSD-95. PKC-induced accumulation of CaMKII was dependent on filamentous actin, whereas dispersal of NMDA receptors occurred by a different mechanism independent of actin or CaMKII. Consistent with the decrease in synaptic density of NMDA receptors, phorbol ester pretreatment reduced excitotoxicity. These results reveal a surprisingly dynamic nature to the molecular composition and functional properties of glutamatergic postsynaptic specializations.
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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Actin Cytoskeleton / metabolism
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Membrane / metabolism
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Cells, Cultured
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Cytoskeleton / metabolism
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Dendrites / metabolism
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Dendrites / ultrastructure
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Disks Large Homolog 4 Protein
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Enzyme Activation / drug effects
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Gene Expression
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Green Fluorescent Proteins
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Intracellular Signaling Peptides and Proteins
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Luminescent Proteins / genetics
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Membrane Proteins
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Nerve Tissue Proteins / metabolism
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism
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Phorbol Esters / pharmacology
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Protein Kinase C / metabolism*
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Protein Transport / drug effects
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Protein Transport / physiology
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Rats
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Receptors, AMPA / metabolism
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Synapses / metabolism*
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Time Factors
Substances
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Disks Large Homolog 4 Protein
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Dlg4 protein, rat
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Intracellular Signaling Peptides and Proteins
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Luminescent Proteins
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Membrane Proteins
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NR1 NMDA receptor
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Nerve Tissue Proteins
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Phorbol Esters
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Receptors, AMPA
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Receptors, N-Methyl-D-Aspartate
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Recombinant Fusion Proteins
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postsynaptic density proteins
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Green Fluorescent Proteins
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Protein Kinase C
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases