Abstract
PSD-95 is a major scaffolding protein of the postsynaptic density, tethering NMDA- and AMPA-type glutamate receptors to signaling proteins and the neuronal cytoskeleton. Here we show that PSD-95 is regulated by the ubiquitin-proteasome pathway. PSD-95 interacts with and is ubiquitinated by the E3 ligase Mdm2. In response to NMDA receptor activation, PSD-95 is ubiquitinated and rapidly removed from synaptic sites by proteasome-dependent degradation. Mutations that block PSD-95 ubiquitination prevent NMDA-induced AMPA receptor endocytosis. Likewise, proteasome inhibitors prevent NMDA-induced AMPA receptor internalization and synaptically induced long-term depression. This is consistent with the notion that PSD-95 levels are an important determinant of AMPA receptor number at the synapse. These data suggest that ubiquitination of PSD-95 through an Mdm2-mediated pathway is critical in regulating AMPA receptor surface expression during synaptic plasticity.
Publication types
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Comparative Study
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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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Acetylcysteine / analogs & derivatives*
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Acetylcysteine / pharmacology
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Analysis of Variance
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Animals
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Animals, Newborn
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Blotting, Western
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Calcium / metabolism
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Cells, Cultured
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Colforsin / pharmacology
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Cysteine Proteinase Inhibitors / pharmacology
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Disks Large Homolog 4 Protein
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Drug Interactions
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Electric Stimulation
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Embryo, Mammalian
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Endocytosis
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Epitopes / metabolism
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Excitatory Amino Acid Agonists / pharmacology
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Hippocampus / cytology
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Hippocampus / drug effects
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Hippocampus / physiology
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Humans
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Immunoglobulin G / metabolism
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Immunohistochemistry
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Immunosuppressive Agents / pharmacology
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In Vitro Techniques
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Intracellular Signaling Peptides and Proteins
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Kidney
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Leupeptins / pharmacology
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Membrane Proteins
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Mutation
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N-Methylaspartate / pharmacology
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Nerve Tissue Proteins / metabolism*
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Neural Inhibition / drug effects
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Neural Inhibition / physiology
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Neurons / drug effects
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Neurons / metabolism*
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Nuclear Proteins*
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Patch-Clamp Techniques
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2
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Rats
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Rats, Long-Evans
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Receptors, AMPA / metabolism*
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Synapses / drug effects
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Synapses / metabolism
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Synapsins / metabolism
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Tacrolimus / analogs & derivatives*
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Tacrolimus / pharmacology
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Time Factors
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Transfection
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Ubiquitin / metabolism*
Substances
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Cysteine Proteinase Inhibitors
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Disks Large Homolog 4 Protein
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Dlg4 protein, rat
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Epitopes
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Excitatory Amino Acid Agonists
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Immunoglobulin G
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Immunosuppressive Agents
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Intracellular Signaling Peptides and Proteins
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Leupeptins
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Membrane Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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Proto-Oncogene Proteins
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Receptors, AMPA
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Synapsins
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Ubiquitin
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postsynaptic density proteins
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lactacystin
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Colforsin
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N-Methylaspartate
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immunomycin
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MDM2 protein, human
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Mdm2 protein, rat
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Proto-Oncogene Proteins c-mdm2
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glutamate receptor ionotropic, AMPA 2
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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Calcium
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Tacrolimus
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Acetylcysteine