PICK1 targets activated protein kinase Calpha to AMPA receptor clusters in spines of hippocampal neurons and reduces surface levels of the AMPA-type glutamate receptor subunit 2.
The PICK1 protein interacts in neurons with the AMPA-type glutamate receptor subunit 2 (GluR2) and with several other membrane receptors via its single PDZ domain. We show that PICK1 also binds in neurons and in heterologous cells to protein kinase Calpha (PKCalpha) and that the interaction is highly dependent on the activation of the kinase. The formation of PICK1-PKCalpha complexes is strongly induced by TPA, and PICK1-PKCalpha complexes are cotargeted with PICK1-GluR2 complexes to spines, where GluR2 is found to be phosphorylated by PKC on serine 880. PICK1 also reduces the plasma membrane levels of the GluR2 subunit, consistent with a targeting function of PICK1 and a PKC-facilitated release of GluR2 from the synaptic anchoring proteins ABP and GRIP. This work indicates that PICK1 functions as a targeting and transport protein that directs the activated form of PKCalpha to GluR2 in spines, leading to the activity-dependent release of GluR2 from synaptic anchor proteins and the PICK1-dependent transport of GluR2 from the synaptic membrane.
Perez
J L
JL
Howard Hughes Medical Institute, Department of Biochemistry, New York University School of Medicine, New York, New York 10016, USA.
Khatri
L
L
Chang
C
C
Srivastava
S
S
Osten
P
P
Ziff
E B
EB
D016475:3T3 Cells; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D006224:Cricetinae; D003598:Cytoskeletal Proteins; D019281:Dimerization; D004789:Enzyme Activation / Q000187:drug effects; D020536:Enzyme Activators / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D011940:Receptor Aggregation; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D020798:Two-Hybrid System Techniques
D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D020536:Enzyme Activators; D007527:Isoenzymes; D046911:Macromolecular Substances; D009687:Nuclear Proteins; C498298:PICK1 protein, rat; C498297:PICk1 protein, human; C091822:Prkcabp protein, mouse; D018091:Receptors, AMPA; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D013755:Tetradecanoylphorbol Acetate; C104722:glutamate receptor ionotropic, AMPA 2