l-683590 and lactacystin

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.

Topics: Acetylcysteine; Analysis of Variance; Animals; Animals, Newborn; Blotting, Western; Calcium; Cells, Cultured; Colforsin; Cysteine Proteinase Inhibitors; Disks Large Homolog 4 Protein; Drug Interactions; Electric Stimulation; Embryo, Mammalian; Endocytosis; Epitopes; Excitatory Amino Acid Agonists; Hippocampus; Humans; Immunoglobulin G; Immunohistochemistry; Immunosuppressive Agents; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Kidney; Leupeptins; Membrane Potentials; Membrane Proteins; Mutation; N-Methylaspartate; Nerve Tissue Proteins; Neural Inhibition; Neurons; Nuclear Proteins; Patch-Clamp Techniques; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-mdm2; Rats; Rats, Long-Evans; Receptors, AMPA; Synapses; Synapsins; Tacrolimus; Time Factors; Transfection; Ubiquitin