Synaptic Glutamate Receptor Trafficking

突触谷氨酸受体贩运

• 批准号: 8660322
• 负责人: ROGER A NICOLL
• 金额: $ 51.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8660322
• 关键词: AMPA Receptors; Address; Affect; Behavior; Binding; Brain; Caenorhabditis elegans; Cells; Chimera organism; Clinical; Disease; Electrophysiology (science); Ensure; Epilepsy; Event; Excitatory Synapse; Family Study; Funding; Gated Ion Channel; Glutamate Receptor; Glutamates; Goals; Grant; Hand; Impaired cognition; Integral Membrane Protein; Kainic Acid Receptors; Kinetics; Knockout Mice; Learning; Ligands; Logic; Measures; Mediating; Membrane; Memory; Modeling; Molecular; Mus; Mutant Strains Mice; Mutation; N-Methyl-D-Aspartate Receptors; Nervous system structure; Neurons; Physiological; Play; Process; Property; Protein Family; Proteins; RNA Interference; Reporting; Research; Role; Site; Slice; Surface; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Time; Work; biophysical properties; density; genetic regulatory protein; granule cell; insight; interest; member; novel; overexpression; postsynaptic; programs; protein complex; receptor; receptor function; research study; stargazin; success; synaptic function; synaptogenesis; therapeutic target; trafficking; transmission process; voltage

DESCRIPTION (provided by applicant): The overall goal of my research program is to elucidate the underlying molecular principles that govern the assembly of the postsynaptic component of a synapse. There are three main questions we wish to address. First, what are the sequences of events that occur during synapse formation? Second, how does a synapse maintain a stable anatomical identity? Finally, what is the mechanism whereby activity can induce a change in synapse function? Central to the understanding of synaptic transmission are the glutamate receptors embedded in the postsynaptic density (PSD). To tackle these ambitious goals we use a combination of a number of techniques. The most central to our studies is electrophysiology, since this is the most critical way to measure the functional consequences of our molecular manipulations. This grant is focused on a variety of proteins that act as glutamate receptor auxiliary subunits. While voltage gated ion channels have long been know to be decorated with auxiliary subunits, which control all aspects of trafficking and function, the notio that ligand gated ion channels also associate with auxiliary subunits is quite new. The most studied family of auxiliary subunits is the TARPs, which selectively control the trafficking and function of the AMPAR subtype of glutamate receptor. However, recent studies indicate that other structurally unrelated proteins, such as CNIH2, CKAMP44, and SynDIG1 also serve as AMPAR auxiliary subunits. In addition, NETO-1/2 has been shown to serve a similar role for kainate receptors. In this renewal we will characterize the role of CNIH2 in the brain with the use of conditional knockout mice. Initial results suggest widespread effects of deleting CNIH2. We will also determine the physiological role of TARP ¿-7, an unusual TARP, which sets it apart from the other well characterize TARPs. Understanding the role of SynDIG1 forms the third Aim of this grant. Both overexpression and RNAi in slice culture will be used for these experiments. Finally we will use the CA1 synapse, which normally lacks kainate receptors, as a null to determine the role of NETO-1/2 in trafficking and gating of kainate receptors. It is hoped that these studies will uncover novel roles for glutamate auxiliary proteins in the nervous system. Given the critical role that receptor trafficking plays in synaptic plasticity it is anticipated tht findings from these studies will have direct clinical impact. Indeed, clinically promising AMPAkines exert their effect, in part, by controlling the kinetics of AMPAR gating similar to TARPs.

描述（由申请人提供）：我的研究计划的总体目标是阐明控制突触后组件组装的基本分子原理。我们希望解决三个主要问题。首先，突触形成过程中发生的事件顺序是什么？其次，突触如何保持稳定的解剖特性？最后，活动引起突触功能变化的机制是什么？理解突触传递的核心是嵌入突触后密度 (PSD) 中的谷氨酸受体。为了实现这些雄心勃勃的目标，我们结合使用了多种技术。我们研究的最核心是电生理学，因为这是测量分子操作的功能后果的最关键方法。这笔资助主要针对充当谷氨酸受体辅助亚基的多种蛋白质。虽然长期以来人们都知道电压门控离子通道被辅助亚基装饰，辅助亚基控制运输和功能的各个方面，但配体门控离子通道也与辅助亚基相关的概念是相当新的。研究最多的辅助亚基家族是 TARP，它选择性地控制谷氨酸受体 AMPAR 亚型的运输和功能。然而，最近的研究表明，其他结构上不相关的蛋白质，如 CNIH2、CKAMP44 和 SynDIG1 也可充当 AMPAR 辅助亚基。此外，NETO-1/2 已被证明对红藻氨酸受体具有类似的作用。在本次更新中，我们将通过使用来描述 CNIH2 在大脑中的作用 条件敲除小鼠。初步结果表明删除 CNIH2 会产生广泛的影响。我们还将确定 TARP ¿-7 的生理作用，这是一种不寻常的 TARP，这使其与其他具有良好特征的 TARP 区分开来。了解 SynDIG1 的作用构成了本次资助的第三个目标。这些实验将使用切片培养物中的过表达和 RNAi。最后，我们将使用通常缺乏红藻氨酸受体的 CA1 突触作为空值来确定 NETO-1/2 在红藻氨酸受体运输和门控中的作用。希望这些研究能够揭示谷氨酸辅助蛋白在神经系统中的新作用。鉴于受体运输在突触可塑性中发挥的关键作用，预计这些研究的结果将产生直接的临床影响。事实上，临床上有前景的 AMPAkine 发挥作用的部分原因是控制与 TARP 类似的 AMPAR 门控动力学。