The synaptic cleft and glutamate receptor trafficking

突触间隙和谷氨酸受体运输

• 批准号: 10449275
• 负责人: ROGER A NICOLL
• 金额: $ 58.43万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449275
• 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.

所有离子型谷氨酸受体都具有相同的结构域结构，具有两个胞外结构域;氨基 末端结构域（ATD）和配体结合结构域（LBD）、跨膜结构域（TM）和胞质结构域（GBD）。 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。几乎所有关于这一主题的工作都集中在不同的CTD上。 谷氨酸受体的亚类。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 没有答案的问题另一方面，关于这些受体的ATD的作用几乎一无所知， 约占蛋白质的50%。 我们最近的研究结果已经确定了ATD在亚单位特异性突触运输中的关键作用，不仅 对于AMPA受体，但也对于红藻氨酸受体和对于Delta 1谷氨酸受体。的总目标 该项目是1）确定一类中亚单位ATD的功能相似性和差异性， 谷氨酸受体以及不同类型受体之间的关系，以及2）鉴定 特异性地与各种谷氨酸受体的细胞外结构域相互作用。完成这些 第一种方法将是进行一系列ATD删除，以确定哪些区域是 为他们的功能所必需。基于我们识别的区域，我们将进行一系列的域交换 实验来确定我们识别的区域是否足以发挥其功能。第二种方法将 重点是识别与谷氨酸受体胞外结构域相互作用的突触间隙蛋白。 这将依赖于候选方法和无偏见的蛋白质组学方法。 具体来说，我们将 1)确定ATD在组成性亚型和亚基特异性离子型谷氨酸受体中的作用 和可塑性依赖的突触靶向; 2)确定GluD 1在兴奋性突触传递中的作用 3)将MDGA蛋白表征为新型ATD结合蛋白 这些结果将提供基本信息的规则和蛋白质参与的细胞外控制 基础和活性依赖性突触谷氨酸受体运输。

项目成果

Mechanisms underlying the synaptic trafficking of the glutamate delta receptor GluD1.

• DOI: 10.1038/s41380-019-0378-4
• 发表时间: 2019-10
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Tao, Wucheng;Ma, Chenxue;Bemben, Michael A.;Li, Kathy H.;Burlingame, Alma L.;Zhang, Mingjie;Nicoll, Roger A.
• 通讯作者: Nicoll, Roger A.

Synaptic memory survives molecular turnover.

• DOI: 10.1073/pnas.2211572119
• 发表时间: 2022-10-18
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Lee, Joel;Chen, Xiumin;Nicoll, Roger A.
• 通讯作者: Nicoll, Roger A.

Synaptic memory and CaMKII.

• DOI: 10.1152/physrev.00034.2022
• 发表时间: 2023-10-01
• 期刊: PHYSIOLOGICAL REVIEWS
• 影响因子: 33.6
• 作者: Nicoll, Roger A.;Schulman, Howard
• 通讯作者: Schulman, Howard

MAGUKs are essential, but redundant, in long-term potentiation

• DOI: 10.1073/pnas.2107585118
• 发表时间: 2021-07-13
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Chen, Xiumin;Fukata, Yuko;Nicoll, Roger A.
• 通讯作者: Nicoll, Roger A.