A role for beta-arrestins in mGluR-dependent plasticity

β-抑制蛋白在 mGluR 依赖性可塑性中的作用

• 批准号: 8771977
• 负责人: GEOFFREY T SWANSON
• 金额: $ 22.5万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8771977
• 关键词: Adrenergic Agents; Agonist; Angiotensins; Animal Disease Models; Area; Arrestins; Brain; Chemosensitization; Coupling; Development; Drug Targeting; Exhibits; Family; Fragile X Syndrome; Frequencies; Future; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; GRM1 gene; GRM5 gene; GTP-Binding Proteins; Goals; Hippocampus (Brain); Investigation; Knock-out; Laboratories; Ligand Binding; Ligands; Link; Mediating; Metabotropic Glutamate Receptors; Neuraxis; Neurons; Neurosciences; Neurotransmitter Receptor; Outcome Study; Pathway interactions; Phosphotransferases; Physiological; Play; Process; Protein Isoforms; Proteins; Publishing; Receptor Signaling; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Signaling Protein; Synapses; Synaptic Transmission; Synaptic plasticity; System; Tail; Testing; adrenergic; arm; arrestin 1; arrestin 2; base; beta-arrestin; desensitization; hippocampal pyramidal neuron; inhibitor/antagonist; insight; knockout animal; mossy fiber; nervous system disorder; neuropathology; neurophysiology; novel; protein activation; public health relevance; receptor; research study; scaffold; seven-transmembrane G-protein-coupled receptor; signal processing; small hairpin RNA; src-Family Kinases; therapeutic target

DESCRIPTION (provided by applicant): Beta-arrestins are cytosolic proteins that interact with the carboxy-terminal tails of seven-transmembrane receptors (i.e., GPCRs) and play a role in desensitization, internalization, and scaffolding other proteins that initiate intracellular signalng cascades independent of G protein activation. Because the latter non-canonical signaling mode is a relatively new discovery, the extent to which beta-arrestins transduce G protein-independent signaling downstream of most types of GPCRs is unknown. Metabotropic glutamate receptors (mGluRs) represent one such family of receptors with a largely uncharacterized relationship to beta-arrestins. In this project, we will test the hypothesis that group I mGluRs (mGluR1 and mGluR5) have the potential to activate b-arrestin-dependent signaling pathways, and that signaling through non-G protein-mediated mechanisms in part underlie mGluR-dependent forms of synaptic plasticity in the hippocampus. In Specific Aim 1, we will determine which group I mGluRs associate with b-arrestin-1 and -2 in the mammalian brain and examine how an mGluR1-dependent form of hippocampal plasticity at mossy fiber - CA3 pyramidal neuron synapses is altered by association with one or both b-arrestins. In Specific Aim 2, we will elucidate which signaling cascades underlie mGluR1-dependent plasticity at mossy fiber synapses. In Specific Aim 3, we will test the role of b-arrestins in a group I mGluR-dependent plasticity at Schaffer collateral - CA1 pyramidal neuron synapses. These experiments have the potential to reveal an unexpected contribution by novel signaling pathways, those downstream of mGluRs but independent of canonical G protein processes, in synaptic plasticity in the hippocampus. The existence of beta-arrestin-dependent signaling would also support the potential development of biased ligands for mGluRs. The outcomes of this study could therefore yield insight into new strategies for therapeutic targeting of group I mGluRs, which in recent years has been pursued for a number of neuropathologies.

描述（由申请人提供）：β-抑制蛋白是胞质蛋白，与七次跨膜受体（即 GPCR）的羧基末端尾部相互作用，并在脱敏、内化和支架其他独立启动细胞内信号级联的蛋白中发挥作用。 G蛋白激活。由于后一种非规范信号传导模式是一个相对较新的发现，因此 β-抑制蛋白在大多数类型的 GPCR 下游转导不依赖于 G 蛋白的信号传导的程度尚不清楚。代谢型谷氨酸受体 (mGluR) 代表了这样一个受体家族，其与 β-抑制蛋白的关系在很大程度上尚未被表征。在这个项目中，我们将测试以下假设：I 组 mGluR（mGluR1 和 mGluR5）有可能激活 b-arrestin 依赖性信号传导途径，并且通过非 G 蛋白介导的机制进行的信号传导在一定程度上是 mGluR 依赖性形式的基础。海马体的突触可塑性。在具体目标 1 中，我们将确定哪一组 I mGluR 与哺乳动物大脑中的 b-arrestin-1 和 -2 相关，并检查苔藓纤维 - CA3 锥体神经元突触处 mGluR1 依赖的海马可塑性形式如何通过与一个或两个b-抑制蛋白。在具体目标 2 中，我们将阐明哪些信号级联是苔藓纤维突触 mGluR1 依赖性可塑性的基础。在具体目标 3 中，我们将测试 β-抑制蛋白在 Schaffer 侧支 - CA1 锥体神经元突触 I 组 mGluR 依赖性可塑性中的作用。这些实验有可能揭示新的信号通路对海马突触可塑性的意想不到的贡献，这些信号通路是 mGluR 的下游但独立于规范的 G 蛋白过程。 β-抑制蛋白依赖性信号传导的存在也将支持 mGluR 偏向配体的潜在开发。因此，这项研究的结果可以深入了解 I 类 mGluR 治疗靶向的新策略，近年来，该策略已被用于许多神经病理学的研究。