Abstract
The scaffold protein PSD-95 promotes the maturation and strengthening of excitatory synapses, functions that require proper localization of PSD-95 in the postsynaptic density (PSD). Here we report that phosphorylation of ser-295 enhances the synaptic accumulation of PSD-95 and the ability of PSD-95 to recruit surface AMPA receptors and potentiate excitatory postsynaptic currents. We present evidence that a Rac1-JNK1 signaling pathway mediates ser-295 phosphorylation and regulates synaptic content of PSD-95. Ser-295 phosphorylation is suppressed by chronic elevation, and increased by chronic silencing, of synaptic activity. Rapid dephosphorylation of ser-295 occurs in response to NMDA treatment that causes chemical long-term depression (LTD). Overexpression of a phosphomimicking mutant (S295D) of PSD-95 inhibited NMDA-induced AMPA receptor internalization and blocked the induction of LTD. The data suggest that synaptic strength can be regulated by phosphorylation-dephosphorylation of ser-295 of PSD-95 and that synaptic depression requires the dephosphorylation of ser-295.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Animals, Newborn
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Cells, Cultured
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Disks Large Homolog 4 Protein
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Postsynaptic Potentials / physiology
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Hippocampus / metabolism*
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Hippocampus / ultrastructure
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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JNK Mitogen-Activated Protein Kinases / metabolism
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Long-Term Synaptic Depression / drug effects
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Long-Term Synaptic Depression / physiology
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Membrane Proteins / chemistry
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mutation / physiology
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N-Methylaspartate / pharmacology
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Organ Culture Techniques
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Phosphorylation / drug effects
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Rats
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Receptors, AMPA / drug effects
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Receptors, AMPA / metabolism
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Serine / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Synaptic Membranes / drug effects
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Synaptic Membranes / metabolism*
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Synaptic Membranes / ultrastructure
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology*
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rac1 GTP-Binding Protein / metabolism
Substances
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Disks Large Homolog 4 Protein
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Dlg4 protein, rat
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Excitatory Amino Acid Agonists
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Receptors, AMPA
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Serine
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N-Methylaspartate
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JNK Mitogen-Activated Protein Kinases
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rac1 GTP-Binding Protein