Glycogen Synthase Kinase 3?-mediated Phosphorylation in the Most C-terminal Region of Protein Interacting with C Kinase 1 (PICK1) Regulates the Binding of PICK1 to Glutamate Receptor Subunit GluA2.
Protein interacting with C kinase 1 (PICK1) is a synaptic protein interacting with the AMPA receptor subunits GluA2/3. The interaction between GluA2 and PICK1 is required for the removal of GluA2 from the synaptic plasma membrane during long-term depression (LTD). It has been suggested that glycogen synthase kinase 3? (GSK-3?) ... is activated during LTD, but the relationships between GluA2, PICK1, and GSK-3? are not well understood. In particular, the substrate(s) of GSK-3? have not yet been determined. Here we showed that PICK1 is a substrate of GSK-3?. We found that Ser(339), Ser(342), Ser(412), and Ser(416) of PICK1 were putative GSK-3?-mediated phosphorylation sites. Among these sites, Ser(416) played a crucial role in regulating the interaction between GluA2 and PICK1. We showed that replacing Ser(416) with Ala disrupted the GluA2-PICK1 interaction, whereas substituting Ser(416) with Glu or Asp retained this interaction. However, deletion of Ser(416) did not affect the GluA2-PICK1 interaction, and substitution of Ser(416) with Ala did not alter the PICK1-PICK1 interaction. Using image analysis in COS-7 cells with AcGFP1-fused PICK1, we showed that substitution of Ser(416) with Ala increased the formation of AcGFP1-positive clusters, suggesting an increase in the association of PICK1 with the membrane. This may have resulted in the dissociation of the GluA2-PICK1 complexes. Our results indicated that GSK-3?-mediated phosphorylation of PICK1 at Ser(416) was required for its association with the AMPA receptor subunit. Therefore, the GSK-3?-mediated phosphorylation of PICK1 may be a regulating factor during LTD induction.
Mesh Terms:
Amino Acid Sequence, Animals, COS Cells, Carrier Proteins, Cell Membrane, Chlorocebus aethiops, Cytoskeletal Proteins, Glutamic Acid, Glycogen Synthase, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Immunoprecipitation, Molecular Sequence Data, Nuclear Proteins, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Rats, Receptors, AMPA, Sequence Homology, Amino Acid, Serine
Amino Acid Sequence, Animals, COS Cells, Carrier Proteins, Cell Membrane, Chlorocebus aethiops, Cytoskeletal Proteins, Glutamic Acid, Glycogen Synthase, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Immunoprecipitation, Molecular Sequence Data, Nuclear Proteins, Phosphorylation, Protein Binding, Protein Structure, Tertiary, Rats, Receptors, AMPA, Sequence Homology, Amino Acid, Serine
J Biol Chem
Date: Dec. 04, 2015
PubMed ID: 26472923
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