Synaptic targeting of AMPA receptors is regulated by a CaMKII site in the first intracellular loop of GluA1

The accumulation of AMPA receptors (AMPARs) at synapses is essential for excitatory synaptic transmission. However, the mechanisms underlying synaptic targeting of AMPARs remain elusive. We have now used a molecular replacement approach on an AMPAR-null background to investigate the targeting mechanisms necessary for regulating AMPAR trafficking in the hippocampus. Although there is an extensive literature on the role of the GluA1 C-tail in AMPAR trafficking, there is no effect of overexpressing the C-tail on basal transmission. Instead, we found that the first intracellular loop domain (Loop1) of GluA1, a previously overlooked region within AMPARs, is critical for receptor targeting to synapses, but not for delivery of receptors to the plasma membrane. We also identified a CaMKII phosphorylation site (S567) in the GluA1 Loop1, which is phosphorylated in vitro and in vivo. Furthermore, we show that S567 is a key residue that regulates Loop1-mediated AMPAR trafficking. Thus, our study reveals a unique mechanism for targeting AMPARs to synapses to mediate synaptic transmission.