Ubiquitination regulates PSD-95 degradation and AMPA receptor surface expression.
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.
Colledge
Marcie
M
Howard Hughes Medical Institute, Vollum Institute, Oregon Health and Science University, Portland, OR 97239, USA.
Snyder
Eric M
EM
Crozier
Robert A
RA
Soderling
Jacquelyn A
JA
Jin
Yetao
Y
Langeberg
Lorene K
LK
Lu
Hua
H
Bear
Mark F
MF
Scott
John D
JD
D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D000076122:Disks Large Homolog 4 Protein; D004347:Drug Interactions; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D004705:Endocytosis; D000939:Epitopes / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney; D007976:Leupeptins / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins; D009154:Mutation; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins; D018408:Patch-Clamp Techniques; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D016704:Synapsins / Q000378:metabolism; D016559:Tacrolimus / Q000031:analogs & derivatives* / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D000939:Epitopes; D018690:Excitatory Amino Acid Agonists; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D007976:Leupeptins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D018091:Receptors, AMPA; D016704:Synapsins; D025801:Ubiquitin; C033652:postsynaptic density proteins; C067713:lactacystin; D005576:Colforsin; D016202:N-Methylaspartate; C058028:immunomycin; C497206:MDM2 protein, human; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2; C104722:glutamate receptor ionotropic, AMPA 2; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D002118:Calcium; D016559:Tacrolimus; D000111:Acetylcysteine