Synaptic Glutamate Receptor Trafficking

突触谷氨酸受体贩运

• 批准号: 8529614
• 负责人: ROGER A NICOLL
• 金额: $ 49.21万
• 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/8529614
• 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; 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（由适用提供）：我的研究计划的总体目标是阐明控制突触的突触后成分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序列是什么？其次，突触如何保持稳定的解剖身份？最后，活动能够引起突触功能的变化的机制是什么？理解突触传播的中心是嵌入突触后密度（PSD）中的谷氨酸受体。为了解决这些雄心勃勃的目标，我们结合了许多技术。我们研究的最重要的是电生理学，因为这是衡量分子操作的功能后果的最关键方法。该赠款集中在多种蛋白质上，这些蛋白质充当谷氨酸受体辅助亚基。虽然长期以来，众所周知，电压门控离子通道都装饰有辅助亚基，这些亚基控制着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联的Notio是很新的。研究最多的辅助亚基家族是粉尘，它有选择地控制谷氨酸受体AMPAR亚型的运输和功能。然而，最近的研究表明，其他结构无关的蛋白质（例如CNIH2，CKAMP44和Syndig1）也用作AMPAR辅助亚基。此外，Neto-1/2已被证明对海谷酸接收器起着相似的作用。在这种续约中，我们将用使用来表征CNIH2在大脑中的作用 有条件的敲除小鼠。初始结果表明删除CNIH2的宽度效果。我们还将确定TARP€-7（一种不寻常的防水布）的物理作用，它使其与其他井的特征性篷布区分开来。了解Syndig1的作用构成了这笔赠款的第三个目标。这些实验将使用切片培养中的过表达和RNAi。最后，我们将使用通常缺乏海谷酸酯受体的CA1突触来确定Neto-1/2在Kainate受体的运输和门控中的作用。希望这些研究能够发现神经系统中谷氨酸辅助蛋白的新作用。鉴于受体运输在突触可塑性中发挥作用的关键作用，这些研究的发现将有直接的临床影响。实际上，临床上有希望的氨基丙烷的作用部分通过控制类似于篷布的AMPAR门控动力学来发挥作用。