Molecular mechanism of synatic vesicle exocytosis-Role of vesicle transport in synaptic plasticity

长期增强（LTP）被认为是理解记忆形成和储存的细胞和分子机制的重要关键。大量研究强烈表明LTP的重要机制涉及突触前细胞谷氨酸释放的改变和突触后谷氨酸受体的反应性。包括谷氨酸在内的神经递质是由突触囊泡胞吐作用释放的，受多种成分的调节，可分为神经递质释放的必需和调节性两大类。Rab3A小G蛋白和Doc2已被证明是调节Ca^<2+>依赖性突触囊泡胞外分泌的调节成分。Rab3A在gdp结合的无活性形式和gtp结合的活性形式之间循环，并在突触前神经末梢的细胞质与突触囊泡膜和突触前质膜之间易位。活化和易位受Rab3 GDIα、Rab3 GAP、Rab3 GEP三种调控因子的调控。我们对Rab gdi α-缺陷小鼠的研究表明，这种蛋白不是基础神经递质释放所必需的，而是调节突触可塑性的。相比之下，Rab3 gep缺陷小鼠表现出更严重的表型，并在出生后因呼吸功能不全而立即死亡。我们从大鼠脑突触囊泡粗片段中分离出一种与Rab3、GEP和GAP共免疫沉淀的新蛋白。这种蛋白被命名为rabconnectin-3，至少结合了Rab3 GEP和GAP。Doc2以二酰基甘油依赖的方式与Munc13相互作用，这种相互作用参与对接过程。我们对Doc2缺陷小鼠的研究表明，该蛋白不是基础神经递质释放所必需的，而是调节突触可塑性的，进一步研究Rab3A和Doc2系统对于理解突触可塑性的分子机制是必要的，突触可塑性可能是学习和记忆的基础

Long-term potentiation (LTP) is believed to provide an important key to understanding the cellular and molecular mechanisms by which 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 resposiveness 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 and Doc2 have been shown to be modulatory components which regulate Ca^<2+>-dependent synaptic vesicle exocytosis. Rab3A cycles between the GDP-bound inactive form and the GTP-bound active form 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 translocation are regulated b … More y three regulators (Rab GDIα, Rab3 GAP, Rab3 GEP). Our studies on Rab GDIα-deficient mice indicate that this protein is not essential for basal neurotransmitter release but regulates synaptic plasticity. In contrast, Rab3 GEP-deficient mice show much more severe phenotypes and die immediately after birth due to respiratory insufficiency. 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. The protein, named rabconnectin-3, bound at least both Rab3 GEP and GAP. Doc2 interacts with Munc13 in a diacylglycerol-dependent manner, and this interaction is involved in the docking process. Our studies on Doc2-deficient mice indicate that this protein is not essential for basal neurotransmitter release but regulates synaptic plasticity Further studies on the Rab3A and Doc2 systems are necessary for understanding of the molecular mechanism of synaptic plasticity, which may underlie learning and memory Less