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Role of the Rab family small G proteins in synaptic plasticity

Rab 家族小 G 蛋白在突触可塑性中的作用

基本信息

批准号：
13470025
负责人：
SASAKI Takuya
金额：
$ 9.28万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13470025/
关键词：
synaptic plasticity vesicle transport Rab3A regulators Rab3 GEP Rab3 GAP Rab GDI Rabconnectin-3 神経伝達物質グルタミン酸受容体神経伝達物質放出 Rab3 GEP

项目摘要

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

长时程增强（LTP）被认为是理解绞车记忆形成和存储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和突触后谷氨酸受体反应性的交替。包括谷氨酸在内的神经递质是通过突触小泡胞吐作用释放的，而突触小泡胞吐作用受到许多成分的调节。它们被分为神经递质释放必需的和调节的。 Rab3A小G蛋白已被证明是调节Ca 2+ 依赖性突触小泡胞吐作用的调节成分。 Rab3A 在 GDP 结合的非活性形式 (GDP-Rab3A) 和 GTP 结合的活性形式 (GTP-Rab3A) 之间循环，并在突触前神经末梢的胞质溶胶与突触小泡的膜和突触前质膜之间易位。激活和易位由三个调节因子（Rab GDI、Rab3 GAP、Rab3 GEP）调节。我们之前对 Rab GDIα 缺陷小鼠的研究表明，Rab GDIα 对于基础神经递质的释放不是必需的，而是通过调节突触可塑性来抑制过度兴奋。在tins研究中，我们发现Rab3 GEP缺陷的小鼠表现出更严重的表型，并在出生后立即因呼吸功能不全而死亡。神经肌肉接头的电子显微镜分析表明，突触小泡和活性区的总数显着减少。我们从大鼠脑的粗突触小泡部分分离出一种新蛋白，该蛋白通过各自的抗体与 Rab3 GEP 和 GAP 进行共免疫沉淀。这种名为 rabconnectin-3 的蛋白质至少结合 Rab3 GEP 和 GAP。大鼠的组织和亚细胞分布分析表明，rabcoitectin-3 在大脑中大量表达，并在突触小泡部分中富集。免疫荧光和免疫电镜显示 rabconnectin-3 集中在突触处的突触小泡上。较少的