The synaptic cleft and glutamate receptor trafficking

突触间隙和谷氨酸受体运输

• 批准号: 10196921
• 负责人: ROGER A NICOLL
• 金额: $ 58.45万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196921
• 关键词: AMPA Receptors; Attention; Brain region; C-terminal; Development; Excitatory Synapse; Extracellular Domain; Glutamate Receptor; Goals; Hippocampus (Brain); Kainic Acid Receptors; Left; Ligand Binding Domain; Modeling; Orphan; Play; Property; Protein Binding Domain; Proteins; Proteomics; Role; Series; Structure; Synapses; Synaptic Cleft; Synaptic Transmission; Transmembrane Domain; Work; base; experience; experimental study; extracellular; novel; polypeptide; receptor; trafficking; virtual

All ionotropic glutamate receptors share the same domain structure with two extracellular domains; the amino terminal domain (ATD) and ligand binding domain (LBD), a transmembrane domain (TM) and a cytoplasmic carboxy terminal domain (CTD). The synaptic trafficking of glutamate receptors is of fundamental importance for synapse development and plasticity. Virtually all the work on this topic has focused on the CTD of the various subclasses of glutamate receptor. These studies, while contributing importantly to our understanding, left many unanswered question. On the other hand virtually nothing is known about the role of the ATDs of these receptors, which account for approximately 50% of the protein. Our recent results have established a critical role of the ATD for the subunit specific synaptic trafficking, not only for AMPA receptors, but also for kainate receptors and for the Delta1 glutamate receptor. The overall goals of this project is to 1) determine the functional similarities and differences of the ATDs of subunits within a class of glutamate receptor as well as between different classes of receptor and 2) identify synaptic cleft proteins that specifically interact with the extracellular domains of the various glutamate receptors. To accomplish these objectives the first approach will be to carry out a series of deletions of the ATD to determine what regions are necessary for their function. Based on the regions we identify, we will carry out a series of domain swapping experiments to determine if the regions we identify are sufficient for their function. The second approach will focus on identifying synaptic cleft proteins that interact with the extracellular domains of the glutamate receptors. This will rely on both a candidate approach and an unbiased proteomic approach. Specifically, we will 1) determine the role of the ATD in subtype- and subunit-specific ionotropic glutamate receptors in constitutive and plasticity-dependent synaptic targeting; 2) determine the role of GluD1 in excitatory synaptic transmission 3) characterize MDGA Proteins as novel ATD binding proteins These results will provide basic information about the rules and proteins involved in the extracellular control of basal and activity-dependent synaptic glutamate receptor trafficking.

所有的离子型谷氨酸受体都具有相同的结构域结构和两个胞外结构域；氨基 末端结构域(ATD)和配体结合域(LBD)、跨膜结构域(TM)和细胞质 羧基末端结构域(CTD)。谷氨酸受体的突触运输对于 突触发育和可塑性。关于这一主题的几乎所有工作都集中在各种不同的CTD 谷氨酸受体亚类。这些研究虽然对我们的理解做出了重要贡献，但也留下了许多 悬而未决的问题。另一方面，关于这些受体的ATD的作用几乎一无所知， 它们约占蛋白质的50%。 我们最近的结果已经确立了ATD对亚单位特异性突触运输的关键作用，不仅是 对于AMPA受体，也对海人酸受体和Delta1谷氨酸受体。的总体目标 本项目的目的是：1)确定一类亚基的ATD的功能异同 谷氨酸受体以及不同类别的受体之间和2)识别突触裂解蛋白 特异性地与各种谷氨酸受体的胞外区域相互作用。要实现这些目标 目标第一种方法是对ATD进行一系列删除，以确定哪些区域 对于他们的功能来说是必要的。根据我们确定的区域，我们将进行一系列的域名互换 用实验来确定我们确定的区域是否足以满足它们的功能。第二种方法将 重点识别与谷氨酸受体胞外区域相互作用的突触裂隙蛋白。 这将依赖于候选方法和不偏不倚的蛋白质组学方法。 具体来说，我们将 1)确定ATD在亚型和亚单位特异性的离子型谷氨酸受体中的作用 可塑性依赖的突触靶向； 2)确定GluD1在兴奋性突触传递中的作用 3)鉴定MDGA蛋白为新的ATD结合蛋白 这些结果将提供有关参与细胞外控制的规则和蛋白质的基本信息 基础和活性依赖的突触谷氨酸受体运输。