RIM IS A PUTATIVE RAB3 EFFECTOR IN REGULATING SYNAPTIC-VESICLE FUSION

Rab3 is a neuronal GTP-binding protein that regulates fusion of synapt ic vesicles and is essential for long-term potentiation of hippocampal messy fibre synapses(1-5). More than thirty Rab GTP-binding proteins are known to function in diverse membrane transport pathways, although their mechanisms of action are unclear. We have now identified a puta tive Rab3-effector protein called Rim. Rim is composed of an amino-ter minal zinc-finger motif and carboxy-terminal PDZ and C-2 domains. It b inds only to GTP (but not to GDP)-complexed Rab3, and interacts with n o other Rab protein tested. There is enrichment of Rab3 and Rim in neu rons, where they have complementary distributions. Rab3 is found only on synaptic vesicles, whereas Rim is localized to presynaptic active z ones in conventional synapses, and to presynaptic ribbons in ribbon sy napses. Transfection of PC12 cells with the amino-terminal domains of Rim greatly enhances regulated exocytosis in a Rab3-dependent manner. We propose that Rim serves as a Rab3-dependent regulator of synaptic-v esicle fusion by forming a GTP-dependent complex between synaptic plas ma membranes and docked synaptic vesicles.