1. Department of Molecular Genetics and Howard Hughes Medical Institute, The University of Texas, Southwestern Medical Center at Dallas, Texas 75235, USA
2. Abteilung IX, Max-Planck-Institut für Experimentelle Medizin, 37075 Göttingen, Germany
3. Swiss Institute for Experimental Cancer Research, 1066 Epalinges, Switzerland

Correspondence to: Thomas C. Südhof¹ Correspondence and requests for materials should be addressed to T.C.S. (e-mail: Email: tsudho@mednet.swmed.edu).

Rab3 is a neuronal GTP-binding protein that regulates fusion of synaptic vesicles and is essential for long-term potentiation of hippocampal mossy fibre synapses^{1, 2, 3, 4, 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 putative Rab3-effector protein called Rim. Rim is composed of an amino-terminal zinc-finger motif and carboxy-terminal PDZ and C₂ domains. It binds only to GTP (but not to GDP)-complexed Rab3, and interacts with no other Rab protein tested. There is enrichment of Rab3 and Rim in neurons, where they have complementary distributions. Rab3 is found only on synaptic vesicles, whereas Rim is localized to presynaptic active zones in conventional synapses, and to presynaptic ribbons in ribbon synapses. 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-vesicle fusion by forming a GTP-dependent complex between synaptic plasma membranes and docked synaptic vesicles.