BRAG1/IQSEC2 as a regulator of small GTPase-dependent trafficking

Precise trafficking events, such as those that underlie synaptic transmission and plasticity, require complex regulation. G-protein signaling plays an essential role in the regulation of membrane and protein trafficking. However, it is not well understood how small GTPases and their regulatory proteins coordinate such specific events. Our recent publication focused on a highly abundant synaptic GEF, BRAG1, whose physiologic relevance was unknown. We find that BRAG1s GEF activity is required for activity-dependent trafficking of AMPARs. Moreover, BRAG1 bidirectionally regulates synaptic transmission in a manner independent of this activity. In addition to the GEF domain, BRAG1 contains several functional domains whose roles are not yet understood but may mediate protein-protein interactions and regulatory effects necessary for its role in regulation of AMPAR trafficking. In this commentary, we explore the potential for BRAG1 to provide specificity of small GTPase signaling, coordinating activity-dependent activation of small GTPase activity with signaling and scaffolding molecules involved in trafficking through its GEF activity and other functional domains.