Role of the Rab family small G proteins in synaptic plasticity

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Long-term potentiation (LTP) is believed to provide an important key to understanding the cellular and molecular mechanisms by winch memories are formed and stored. Numerous studies strongly suggest that important mechanisms underlying LTP involves alternations in the release of glutamate from the presynaptic cells and the responsiveness of the postsynaptic glutamate receptors. Neurotransmitters including glutamate are released by synaptic vesicle exocytosis which is regulated by many components. They are classified into essential and modulatory ones for neurotransmitter release. Rab3A small G protein has been shown to be a modulatory component which regulates Ca^<2+>-dependent synaptic vesicle exocytosis. Rab3A cycles between the GDP-bound inactive form (GDP-Rab3A) and the GTP-bound active form (GTP-Rab3A) and translocates between the cytosol of the presynaptic nerve terminal and the membranes of synaptic vesicles and the presynaptic plasma membrane. The activation and the translocati … More on are regulated by three regulators (Rab GDI, Rab3 GAP, Rab3 GEP). Our previous studies on Rab GDIα-deficient mice had revealed that Rab GDIα is not essential for basal neurotransmitter release but suppress hyperexcitability via modulation of synaptic plasticity. In tins study, we found that Rab3 GEP-deficient mice show much more severe phenotypes and die immediately after birth due to respiratory insufficiency. Electron microscopic analysis of the neuromuscular junction revealed that total numbers of synaptic vesicles and active zones are markedly reduced. We isolated a novel protein that was co-immunoprecipitated with Rab3 GEP and GAP by their respective antibodies from the crude synaptic vesicle fraction of rat brain. This protein, named rabconnectin-3, bound at least both Rab3 GEP and GAP. Tissue and subcellular distribution analyses in rat indicated that rabcoithectin-3 was abundantly expressed in the brain where it was enriched in the synaptic vesicle fraction. Immunofluorescence and immunoelectron microscopy revealed that rabconnectin-3 was concentrated on synaptic vesicles at synapses. Less