Role of endosomal sorting machinery controlling AMPA receptors trafficking in the hippocampus

Resumo

Trafficking of glutamatergic AMPA receptors (AMPAR) plays a crucial role in modulating synaptic transmission in the hippocampus. AMPAR density at postsynaptic sites is thought to be determined by a combination of constitutive and signal-regulated protein trafficking pathways that comprise of polarized sorting from the trans golgi network (TGN) to somatodendritic membranes, endocytosis, endosomal recycling and Iysosomal targeting. Sorting of transmembrane proteins at the plasma membrane, the TGN and endosomes is mediated by interactions of sorting-motifs present in the cytosolic tail of transmembrane proteins with adaptor molecules that are components of vesicle coats. Consistently, the cytosolic tail of AMPAR subunits was shown to contain information crucial for sorting. The four family members of heterotetrameric adaptor protein (AP) complexes mediate protein sorting at the late secretory pathway, and have been implicated in transport of AMPAR. GluA2 binds specifically to AP-2 and this interaction is required for GluA2 internalization following long-term depression stimuli. We have recently discovered a new interaction between endogenous activity-regulated cytoskeleton (Arc, also known as Arg3.1) Arc/Arg3.1 protein and the AP-2 complex. Over the past decade, findings from several studies showed that Arc/Arg3.1 controls changes in synaptic transmission by increasing endocytosis of AMPAR subunits 1 and 2. However, the direct link between Arc/Arg3.1 expression and the incorporation of AMPAR into the endocytotic machinery has not yet been shown. AP-2 could be the link missing as it binds directly to AMPAR subunit 2. Therefore, the main aim of this proposal is to confirm the interaction between AP-2 and Arc/Arg3.1 protein and show its functional role on surface expression of AMPAR subunits. (AU)