PICK1 targets activated protein kinase C alpha to AMPA receptor clusters in spines of hippocampal neurons and reduces surface levels of the AMPA-typeglutamate receptor subunit 2

The PICK1 protein interacts in neurons with the AMPA-type glutamate recepto r subunit 2 (GluR2) and with several other membrane receptors via its singl e PDZ domain. We show that PICK1 also binds in neurons and in heterologous cells to protein kinase C alpha (PKC alpha) and that the interaction is hig hly dependent on the activation of the kinase. The formation of PICK1-PKC a lpha complexes is strongly induced by TPA, and PICK1-PKC alpha complexes ar e cotargeted with PICK1-GluR2 complexes to spines, where GluR2 is found to be phosphorylated by PKC on serine 880. PICK1 also reduces the plasma membr ane levels of the GluR2 subunit, consistent with a targeting function of PI CK1 and a PKC-facilitated release of GluR2 from the synaptic anchoring prot eins ABP and GRIP. This work indicates that PICK1 functions as a targeting and transport protein that directs the activated form of PKC alpha to GluR2 in spines, leading to the activity-dependent release of GluR2 from synapti c anchor proteins and the PICK1-dependent transport of GluR2 from the synap tic membrane.