Conformational mechanisms of mGluR gating and regulation

mGluR 门控和调节的构象机制

• 批准号: 10298420
• 负责人: Ehud Isacoff
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10298420
• 关键词: Affinity; Allosteric Regulation; Arrestins; Biological Assay; Brain; Cells; Coupled; Diffusion; Drug Targeting; Enzymes; Fluorescence Resonance Energy Transfer; G-Protein-Coupled Receptors; GTP-Binding Proteins; Glutamates; Goals; Heterodimerization; Homo; Hybrids; Intercellular Junctions; Label; Ligands; Membrane; Metabotropic Glutamate Receptors; Methods; Modeling; Molecular; Molecular Conformation; Monitor; Nervous system structure; Neuroglia; Neurotransmitter Receptor; Neurotransmitters; Optical Methods; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Property; Proteins; Pump; Receptor Activation; Receptor Signaling; Regulation; Rotation; Signal Transduction; Signaling Protein; Site; Stimulus; Structure; Subgroup; Synapses; Synaptic Cleft; Synaptic Transmission; Tertiary Protein Structure; Testing; Work; design; dimer; drug development; extracellular; fascinate; member; nervous system disorder; neurotransmitter release; positive allosteric modulator; postsynaptic; presynaptic; presynaptic neurons; receptor; receptor function; response; spatiotemporal

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。