AGAP3 and Arf6 regulate trafficking of AMPA receptors and synaptic plasticity.

During NMDA receptor-mediated long-term potentiation (LTP), synapses are strengthened by trafficking AMPA receptors to the synapse through a calcium-dependent kinase cascade following activation of NMDA receptors. This process results in a long-lasting increase in synaptic strength that is thought to be a cellular mechanism for learning and memory. Over the past 20 years, many signaling pathways have been shown to be involved in the induction and maintenance of LTP including the MAPK cascade. However, the crucial link between NMDA receptors and the signaling cascades involved in AMPA receptor trafficking during LTP remains elusive. In this study, we aimed to identify and characterize NMDA receptor signaling proteins that link NMDA receptor activation to downstream signaling pathways that lead to trafficking of AMPA receptors. We have identified a novel NMDA receptor interacting signaling protein, AGAP3. AGAP3 contains multiple signaling domains, a GTPase-like domain, a pleckstrin homology domain, and an ArfGAP domain, and exists as a component of the NMDA receptor complex. In addition, we found that AGAP3 regulates NMDA receptor-mediated Ras/ERK and Arf6 signaling pathways during chemically induced LTP in rat primary neuronal cultures. Finally, knocking down AGAP3 expression leads to occlusion of AMPA receptor trafficking during chemically induced LTP. Together, AGAP3 is an essential signaling component of the NMDA receptor complex that links NMDA receptor activation to AMPA receptor trafficking.