SYNAPTOTAGMIN/SV2 COMPLEX--ROLE IN NEUROTRANSMISSION

钙调节的神经递质的分泌是主要的 神经系统中的沟通方式。神经递质的分泌是 由一个独特的细胞器，突触小泡介导，它经历 重复的充填、靶向、引爆、胞吐和内吞 在突触前终末。其中几个阶段是通过 蛋白质复合体的顺序形成和解离。识别 所涉及的蛋白质复合体，决定了每个蛋白质复合体在囊泡周期中的位置 复杂的行为，并描述钙是如何调节它们的行为的 了解神经递质的分子机制 放手。申请者和她的学生已经鉴定出一种蛋白质复合体 它含有突触囊泡蛋白SV2和突触聚集蛋白。SV2是一种 转运蛋白样膜糖蛋白被认为是一种 小分子转运体或作为融合孔的组成部分 启动发射机释放。突触素是一种钙结合蛋白 是正常的钙调节胞吐所必需的。这些东西的存在 所有突触中的蛋白质，以及观察到的钙 调节它们的相互作用，表明SV2突触素复合体 在神经递质的分泌中起着至关重要的作用。以确定该角色 申请者提出了四个目标，旨在确定生理 复合体的功能以及该功能是如何被调节的。1. 申请者将确定SV2突触结合蛋白复合体的成分。 2.申请人将测试SV2-突触凝集素的破坏效果 PC12细胞调节分泌的相互作用。3.申请人将 测试突触素的所有八种亚型是否都表现出 与SV2的钙依赖相互作用。4.申请人将决定 磷酸化是否调节SV2和突触素的相互作用。 这些研究将提供必要的基本信息，以了解 作为学习和记忆基础的突触效能的变化 作为多种神经病变。

DESCRIPTION Calcium-regulated secretion of neurotransmitters is the primary mode of communication in the nervous system. Neurotransmitter secretion is mediated by a unique organelle, the synaptic vesicle, which undergoes repetitive rounds of filling, targeting, priming, exocytosis and endocytosis in the presynaptic terminal. Several of these stages are accomplished via the sequential formation and dissociation of protein complexes. Identifying the protein complexes involved, determining where in the vesicle cycle each complex acts and describing how calcium regulates their action is therefore central to understanding the molecular mechanisms of neurotransmitter release. The applicant and her students have identified a protein complex that contains the synaptic vesicle proteins SV2 and synaptotagmin. SV2 is a transporter-like membrane glycoprotein hypothesized to function either as a small molecule transporter or as a component of the fusion pore that initiates transmitter release. Synaptotagmin is a calcium-binding protein required for normal calcium-regulated exocytosis. The presence of these proteins in all synapses, together with the observation that calcium regulates their interaction, suggests that the SV2 synaptotagmin complex plays a crucial role in neurotransmitter secretion. To identify that role the applicant proposes four aims designed to determine the physiological function of the complex and how that function is regulated. 1. The applicant will determine the components of the SV2 synaptotagmin complex. 2. The applicant will test the effect of disruption of SV2-synaptotagmin interaction on regulated secretion in PC12 cells. 3. The applicant will test whether all eight isoforms of synaptotagmin demonstrate calcium-dependent interactions with SV2. 4. The applicant will determine whether phosphorylation regulates the interaction of SV2 and synaptotagmin. These studies will provide basic information required to understand the changes in synaptic efficacy that underlie both learning and memory as well as multiple neuropathologies.