title: Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins.
abstract: PSD-95, DLG, ZO-1 (PDZ) domain-mediated protein interactions have been shown to play important roles in the regulation of glutamate receptor function at excitatory synapses. Recent studies demonstrating the rapid regulation of AMPA receptor function during synaptic plasticity have suggested that AMPA receptor interaction with PDZ domain-containing proteins may be dynamically modulated. Here we show that PKC phosphorylation of the AMPA receptor GluR2 subunit differentially modulates its interaction with the PDZ domain-containing proteins GRIP1 and PICK1. The serine residue [serine-880 (Ser880)] in the GluR2 C-terminal sequence (IESVKI) critical for PDZ domain binding is a substrate of PKC and is phosphorylated in vivo. In vitro binding and coimmunoprecipitation studies show that phosphorylation of serine-880 within the GluR2 PDZ ligand significantly decreases GluR2 binding to GRIP1 but not to PICK1. Immunostaining of cultured hippocampal neurons demonstrates that the Ser880-phosphorylated GluR2 subunits are enriched and colocalized with PICK1 in the dendrites, with very little staining observed at excitatory synapses. Interestingly, PKC activation in neurons increases the Ser880 phosphorylation of GluR2 subunits and recruits PICK1 to excitatory synapses. Moreover, PKC stimulation in neurons results in rapid internalization of surface GluR2 subunits. These results suggest that GluR2 phosphorylation of serine-880 may be important in the regulation of the AMPA receptor internalization during synaptic plasticity.
authors.affiliation: Department of Neuroscience, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: H J
authors.initials: HJ
authors.lastname: Chung
authors.forename: J
authors.initials: J
authors.lastname: Xia
authors.forename: R H
authors.initials: RH
authors.lastname: Scannevin
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: R L
authors.initials: RL
authors.lastname: Huganir
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008024:Ligands; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D051958:Nuclear Receptor Coactivator 2; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051381:Rats; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D008024:Ligands; C498001:NCOA2 protein, human; C498003:Ncoa2 protein, rat; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D051958:Nuclear Receptor Coactivator 2; C498298:PICK1 protein, rat; C498297:PICk1 protein, human; D018091:Receptors, AMPA; D014157:Transcription Factors; D012694:Serine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; C104722:glutamate receptor ionotropic, AMPA 2