title: Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95.
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.
authors.affiliation: The Picower Institute for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Myung Jong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Kensuke
authors.initials: K
authors.lastname: Futai
authors.forename: Jihoon
authors.initials: J
authors.lastname: Jo
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Kwangwook
authors.initials: K
authors.lastname: Cho
authors.forename: Morgan
authors.initials: M
authors.lastname: Sheng
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D016202:N-Methylaspartate / Q000494:pharmacology; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D018690:Excitatory Amino Acid Agonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018091:Receptors, AMPA; D012694:Serine; D016202:N-Methylaspartate; D048031:JNK Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein