Conformational mechanisms of mGluR gating and regulation
mGluR 门控和调节的构象机制
基本信息
- 批准号:10298420
- 负责人:
- 金额:$ 40.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-15 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffinityAllosteric RegulationArrestinsBiological AssayBrainCellsCoupledDiffusionDrug TargetingEnzymesFluorescence Resonance Energy TransferG-Protein-Coupled ReceptorsGTP-Binding ProteinsGlutamatesGoalsHeterodimerizationHomoHybridsIntercellular JunctionsLabelLigandsMembraneMetabotropic Glutamate ReceptorsMethodsModelingMolecularMolecular ConformationMonitorNervous system structureNeurogliaNeurotransmitter ReceptorNeurotransmittersOptical MethodsPathway interactionsPharmaceutical PreparationsPharmacologyPropertyProteinsPumpReceptor ActivationReceptor SignalingRegulationRotationSignal TransductionSignaling ProteinSiteStimulusStructureSubgroupSynapsesSynaptic CleftSynaptic TransmissionTertiary Protein StructureTestingWorkdesigndimerdrug developmentextracellularfascinatemembernervous system disorderneurotransmitter releasepositive allosteric modulatorpostsynapticpresynapticpresynaptic neuronsreceptorreceptor functionresponsespatiotemporal
项目摘要
SUMMARY/ABSTRACT
G-protein–coupled receptors (GPCRs), the largest class of membrane signaling proteins, respond to a wide
array of extracellular stimuli to initiate intracellular signaling via G proteins and arrestins. Recent studies have
provided snapshots of GPCR structures in distinct conformations and revealed that they are extremely
dynamic. The conformational dynamics appear to be central to ligand recognition, activation and signaling.
Membrane receptors have evolved to respond to precise spatio-temporal concentration profiles of extracellular
ligands. In the nervous system, neurotransmitter receptors encounter a wide range of neurotransmitter
concentrations and spatio-temporal profiles. Key factors are the small extracellular volume of the synaptic cleft,
pumps and/or enzymes that remove neurotransmitter, and diffusion. Additionally, neurotransmitter receptors
can be localized within the synapse both pre- and postsynaptically, as well as extrasynaptically where they can
encounter neurotransmitter released either locally, which briefly reaches low millimolar levels within the cleft,
and spillover from nearby synapses, which reaches lower concentrations. Metabotropic glutamate receptors
(mGluRs) are found pre- and postsynaptically at excitatory glutamatergic synapses, as well as on glia and at
inhibitory GABAergic presynaptic nerve terminals, meaning that they are activated by both high local
concentrations near the site of release and spillover. mGluRs of various kinds can be found together in
presynaptic nerve terminals, even when they are all coupled to the same G protein. And they can dimerize,
generating hybrid or in some cases totally unique properties and pharmacological profiles. To understand what
each mGluR subtype does and develop effective drugs to treat the neurological disorders in which they are
implicated, we need to understand how they function and how they are regulated. Our goal here is to define
the molecular mechanisms that set and regulate the functional properties of homo- and heteromeric mGluRs at
synapses and put into place assays that can be used to screen modulation in the nervous system.
摘要/摘要
G蛋白偶联受体(GPCRs)是最大的一类膜信号蛋白,可广泛地
一系列细胞外刺激,通过G蛋白和阻滞素启动细胞内信号传递。最近的研究表明
提供了不同构象的GPCR结构的快照,并揭示了它们非常
活力四射。构象动力学似乎是配体识别、激活和信号传递的中心。
膜受体已经进化为对细胞外精确的时空浓度曲线做出反应
配基。在神经系统中,神经递质受体遇到广泛的神经递质。
浓度和时空分布。关键因素是突触裂隙的小细胞外体积,
泵和/或酶,以消除神经递质和扩散。此外,神经递质受体
可以在突触前和突触后以及在可能的情况下在突触外定位于突触内
遇到局部释放的神经递质,在裂隙内短暂达到低毫摩尔水平,
以及来自附近突触的溢出,达到较低的浓度。代谢型谷氨酸受体
(MGluR)在兴奋性谷氨酸能突触的突触前和突触后,以及在胶质细胞和
抑制性GABA能突触前神经末梢,意味着它们被两个高位局部激活
释放和溢出地点附近的浓度。各种类型的mGluR都可以在
突触前神经末梢,即使它们都与相同的G蛋白相连。它们可以进行二聚化,
产生杂交的或在某些情况下完全独特的特性和药理特性。要了解什么
每一种mGluR亚型都会研发有效的药物来治疗他们所在的神经疾病
牵涉其中,我们需要了解它们是如何运作的,以及它们是如何受到监管的。我们在这里的目标是定义
决定和调节同、异构体mGluRs功能特性的分子机制
突触和到位的分析,可以用来筛选神经系统的调制。
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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Ehud Isacoff其他文献
Ehud Isacoff的其他文献
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{{ truncateString('Ehud Isacoff', 18)}}的其他基金
Conformational mechanisms of mGluR gating and regulation
mGluR 门控和调节的构象机制
- 批准号:
10665636 - 财政年份:2021
- 资助金额:
$ 40.13万 - 项目类别:
Conformational mechanisms of mGluR gating and regulation
mGluR 门控和调节的构象机制
- 批准号:
10443878 - 财政年份:2021
- 资助金额:
$ 40.13万 - 项目类别:
Synaptic to circuit homeostasis in the Drosophila locomotor system
果蝇运动系统中的突触与电路稳态
- 批准号:
10654556 - 财政年份:2019
- 资助金额:
$ 40.13万 - 项目类别:
Synaptic to circuit homeostasis in the Drosophila locomotor system
果蝇运动系统中的突触与电路稳态
- 批准号:
10438585 - 财政年份:2019
- 资助金额:
$ 40.13万 - 项目类别:
Synaptic to circuit homeostasis in the Drosophila locomotor system
果蝇运动系统中的突触与电路稳态
- 批准号:
10210452 - 财政年份:2019
- 资助金额:
$ 40.13万 - 项目类别:
Novel tools for cell-specific imaging of functional connectivity and circuit operations
用于功能连接和电路操作的细胞特异性成像的新工具
- 批准号:
9343283 - 财政年份:2015
- 资助金额:
$ 40.13万 - 项目类别:
Novel tools for cell-specific imaging of functional connectivity and circuit operations
用于功能连接和电路操作的细胞特异性成像的新工具
- 批准号:
9036880 - 财政年份:2015
- 资助金额:
$ 40.13万 - 项目类别:
Optical control of synaptic transmission for in vivo analysis of brain circuits and behavior
突触传递的光学控制用于脑回路和行为的体内分析
- 批准号:
8934227 - 财政年份:2014
- 资助金额:
$ 40.13万 - 项目类别:
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