REVIEW - RAB3A-RABGDI-RABPHILIN-3A SYSTEM REGULATING MEMBRANE-FUSION MACHINERY IN THE SYNAPSE AND THE GROWTH CONE

Neurotransmitter release in the synapse is accomplished by the vesicular exocytosis, the membrane fusion between the synaptic vesicles and the presynaptic plasma membrane. At least three molecular systems are involved in the membrane fusion in the synapse: the Rab3A-RabGDI-Rabphilin-3A system, the NSF-SNAP-SNARE system, and the fusion pore formation system. In the first system, Rab3A, a small GTP-binding protein, functions in two interconvertible forms like a molecular switch: the GDP-bound inactive ''off'' form which is recognized by Rab GDP dissociation inhibitor (GDI) and the GTP-bound active ''on'' form which is recognized by Rabphilin-3A, RabGDI specifically binds to the GDP-bound ''off'' form of Rab3A and translocates it from the membrane to the cytoplasm. Rabphilin-3A localized on the membrane specifically binds to the GTP-bound ''on'' form. Whether Rab3A is in the form of the GTP-bound ''on'' or the GDP-bound ''off'' clearly determines its own localization on the membrane or in the cytoplasm. By immunoelectron microscopy, Rab3A is indeed localized at the synaptic vesicles, the presynaptic plasma membrane, and the cytoplasm near the active zones, where the membrane fusion takes place. Taken together, Rab3A-RabGDI-Rabphilin-3A system probably regulates the targeting and docking of the synaptic vesicles at the active zone. The NSF-SNAP-SNARE system further forms a vesicle fusion apparatus. Finally, the fusion pore formation system directly forms the channel between the synaptic vesicle and the presynaptic plasma membrane, through which neurotransmitter is released. In the nerve growth cone, a membrane fusion machinery similar to that in the synapse may be involved in the plasmalemmal expansion of the growth cone. For further histochemical approaches toward the molecular architecture of the membrane fusion machinery, the stoichiometric detection of the proteins by the immunoelectron microscopy with a modified pre-embedding 1-nm gold particle (nanogold)-silver enhancement method is very useful.