Role of PICK1 in AMPA Receptor Transport
PICK1 在 AMPA 受体转运中的作用
基本信息
- 批准号:7163462
- 负责人:
- 金额:$ 49.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-01-01 至 2008-12-31
- 项目状态:已结题
- 来源:
- 关键词:AMPA ReceptorsATP HydrolysisAgonistBindingBiological AssayC-terminalCell membraneChemicalsChemosensitizationChromosome PairingComplexCytoplasmic TailDependenceDestinationsDisruptionDominant-Negative MutationEmploymentEndocytosisEndoplasmic ReticulumEndosomesExcitatory SynapseGTP-Binding ProteinsGluR2 subunit AMPA receptorHippocampus (Brain)LigandsLinkLocationLong-Term DepressionMembraneMemoryMutagenesisN-ethylmaleimide-sensitive proteinPhosphotransferasesPhysiologicalProtein BindingProtein Kinase CProteinsPublicationsRateRecyclingRegulationRelative (related person)RoleSNAP receptorSourceStimulusSynapsesSynaptic MembranesSynaptic ReceptorsTertiary Protein StructureTorqueVesicleWorkalpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acidamino 3 hydroxy 5 methylisoxazole 4 propionatebasehippocampal pyramidal neuronin vivonovelprotein functionreceptorsoluble NSF attachment proteintraffickingtransmission process
项目摘要
DESCRIPTION (provided by applicant): We will study the roles of PICK1 (Protein Interacting with C Kinase-1) and its regulator, NSF (N-ethylmaleimide Sensitive Factor) in AMPA receptor (AMPAR) trafficking. AMPAR are the major source of excitatory currents in the CNS and changes in AMPAR synaptic abundance regulate synaptic strength. PICK1 and NSF bind to the C-terminal, cytoplasmic domain of the AMPAR GluR2 subunit, and have opposing roles in controlling AMPAR synaptic levels. PICK1 binds to GluR2 via a PDZ domain and colocalizes with AMPAR in endosome-like vesicles in hippocampal pyramidal neurons. PICK1 expression reduces AMPAR synaptic membrane abundance and PICK is implicated in the mechanism of long term depression (LTD), all indicating a role for PICK1 in AMPAR endocytosis. NSF, together with the SNAP proteins, is known for dissociating SNARE complexes. In the case of AMPAR, the interaction of NSF with GluR2 is necessary for maintaining AMPAR currents and synaptic abundance. Our recent work has revealed a novel function for NSF. NSF binds together with the SNAPs to the PICK1-GluR2 complex and displaces PICK1 from GluR2. By displacing an endocytosis factor, NSF maintains AMPAR in the synapse. The Aims of this project are: 1) To determine the structural basis for assembly of the GluR2-PICK1-NSF-SNAP complex and its disassembly by NSF. We will define protein-protein contacts that stabilize the complex and determine whether the SNAPs transmit rotational torque from NSF to PICK1 during disassembly. We will determine the basis for the differential ability of alpha- and beta-SNAPs to disrupt PICK1-GluR2 complexes. 2) To determine the role of PICK1 in AMPAR trafficking. We will identify the starting and destination membranes and the roles of G proteins in the transport mechanism. 3) To determine regulation in vivo by physiologic stimuli, including the role of PICK1 in GluR2/GluR3 constitutive recycling. These studies will reveal basic mechanisms relevant to synapse regulation and memory formation.
描述(由申请人提供):我们将研究PICK 1(与C激酶-1相互作用的蛋白质)及其调节因子NSF(N-乙基马来酰亚胺敏感因子)在AMPA受体(AMPAR)运输中的作用。AMPAR是CNS中兴奋性电流的主要来源,AMPAR突触丰度的变化调节突触强度。PICK 1和NSF与AMPAR GluR 2亚基的C-末端胞质结构域结合,在控制AMPAR突触水平方面具有相反的作用。PICK 1通过PDZ结构域与GluR 2结合,并与海马锥体神经元内体样囊泡中的AMPAR共定位。PICK 1表达减少AMPAR突触膜丰度,PICK参与长期抑制(LTD)机制,所有这些都表明PICK 1在AMPAR内吞作用中的作用。已知NSF与SNAP蛋白一起解离SNARE复合物。在AMPAR的情况下,NSF与GluR 2的相互作用对于维持AMPAR电流和突触丰度是必要的。我们最近的工作揭示了NSF的一个新功能。NSF与SNAP一起结合到PICK 1-GluR 2复合物上,并从GluR 2中置换PICK 1。通过取代内吞作用因子,NSF在突触中维持AMPAR。本研究的目的是:1)确定GluR 2-PICK 1-NSF-SNAP复合物的组装和NSF对其的拆卸的结构基础。我们将定义蛋白质-蛋白质接触,以稳定复合物,并确定SNAP是否在拆卸过程中将旋转扭矩从NSF传递到PICK 1。我们将确定α-和β-SNAP破坏PICK 1-GluR 2复合物的差异能力的基础。2)确定PICK 1在AMPAR贩运中的作用。我们将确定起始和目的地膜和G蛋白在运输机制中的作用。3)确定体内生理刺激的调节,包括PICK 1在GluR 2/GluR 3组成性再循环中的作用。这些研究将揭示与突触调节和记忆形成相关的基本机制。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('EDWARD B ZIFF', 18)}}的其他基金
Calcium Permeable AMPA Receptors: Signaling, Toxicity and Control
钙渗透性 AMPA 受体:信号传导、毒性和控制
- 批准号:
8674399 - 财政年份:2013
- 资助金额:
$ 49.14万 - 项目类别:
Role of cGKII in AMPA Receptor Transport
cGKII 在 AMPA 受体转运中的作用
- 批准号:
8718570 - 财政年份:2013
- 资助金额:
$ 49.14万 - 项目类别:
Calcium Permeable AMPA Receptors: Signaling, Toxicity and Control
钙渗透性 AMPA 受体:信号传导、毒性和控制
- 批准号:
8197915 - 财政年份:2009
- 资助金额:
$ 49.14万 - 项目类别:
Calcium Permeable AMPA Receptors: Signaling, Toxicity and Control
钙渗透性 AMPA 受体:信号传导、毒性和控制
- 批准号:
8007372 - 财政年份:2009
- 资助金额:
$ 49.14万 - 项目类别:
Calcium Permeable AMPA Receptors: Signaling, Toxicity and Control
钙渗透性 AMPA 受体:信号传导、毒性和控制
- 批准号:
7590880 - 财政年份:2009
- 资助金额:
$ 49.14万 - 项目类别:
Calcium Permeable AMPA Receptors: Signaling, Toxicity and Control
钙渗透性 AMPA 受体:信号传导、毒性和控制
- 批准号:
8415898 - 财政年份:2009
- 资助金额:
$ 49.14万 - 项目类别:
Role of cGKII in AMPA Receptor Transport
cGKII 在 AMPA 受体转运中的作用
- 批准号:
8440838 - 财政年份:2003
- 资助金额:
$ 49.14万 - 项目类别:
Role of cGKII in AMPA Receptor Transport
cGKII 在 AMPA 受体转运中的作用
- 批准号:
7821335 - 财政年份:2003
- 资助金额:
$ 49.14万 - 项目类别:
Role of cGKII in AMPA Receptor Transport
cGKII 在 AMPA 受体转运中的作用
- 批准号:
7654751 - 财政年份:2003
- 资助金额:
$ 49.14万 - 项目类别:
Role of PICK1 in AMPA Receptor Transport
PICK1 在 AMPA 受体转运中的作用
- 批准号:
6570215 - 财政年份:2003
- 资助金额:
$ 49.14万 - 项目类别:
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