Trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptor subunit GluA2 from the endoplasmic reticulum is stimulated by a complex containing Ca2+/calmodulin-activated kinase II (CaMKII) and PICK1 protein and by release of Ca2+ from internal stores.

The GluA2 subunit of the AMPA receptor (AMPAR) dominantly blocks AMPAR Ca(2+) permeability, and its trafficking to the synapse regulates AMPAR-dependent synapse Ca(2+) permeability. Here we show that GluA2 trafficking from the endoplasmic reticulum (ER) to the plasma membrane of cultured hippocampal neurons requires Ca(2+) release from internal stores, the activity of Ca(2+)/calmodulin activated kinase II (CaMKII), and GluA2 interaction with the PDZ protein, PICK1. We show that upon Ca(2+) release from the ER via the IP3 and ryanodine receptors, CaMKII that is activated enters a complex that contains PICK1, dependent upon the PICK1 BAR (Bin-amphiphysin-Rvs) domain, and that interacts with the GluA2 C-terminal domain and stimulates GluA2 ER exit and surface trafficking. This study reveals a novel mechanism of regulation of trafficking of GluA2-containing receptors to the surface under the control of intracellular Ca(2+) dynamics and CaMKII activity.