Regulation of Metabotropic glutamate Receptor Signaling by Caveolar Rafts

小凹筏对代谢型谷氨酸受体信号传导的调节

• 批准号: 8060472
• 负责人: ANNA FRANCESCONI
• 金额: $ 41.09万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8060472
• 关键词: AMPA Receptors; Adaptor Signaling Protein; Adenylate Cyclase; Alzheimer' s Disease; Attenuated; Axon; Binding; Brain; Brain region; Caveolae; Cell membrane; Cell surface; Cocaine Dependence; Complex; Coupling; Cyclic AMP-Dependent Protein Kinases; Dendrites; Development; Disease; Drug Addiction; Epilepsy; Event; Excitatory Synapse; Fragile X Syndrome; G-Protein-Coupled Receptors; GTP-Binding Proteins; Glutamates; Health; Hippocampus (Brain); Impairment; Inherited; Knockout Mice; Link; Long-Term Depression; Long-Term Potentiation; MAP Kinase Gene; Maintenance; Membrane; Membrane Microdomains; Membrane Proteins; Memory; Mental Retardation; Mental disorders; Messenger RNA; Metabotropic Glutamate Receptors; Modification; Molecular; Morphology; Neurons; Parkinson Disease; Pathway interactions; Phospholipase C; Physiological; Play; Protein Biosynthesis; Protein Subunits; Protein Tyrosine Kinase; Proteins; Psyche structure; Receptor Signaling; Regulation; Research; Role; Scaffolding Protein; Schizophrenia; Signal Transduction; Signaling Protein; Site; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Translations; Vertebral column; Work; addiction; caveolin 1; classical conditioning; insight; nervous system disorder; neural circuit; neuronal circuitry; neuropsychiatry; neurotransmission; neurotransmitter release; postsynaptic; presynaptic; receptor; research study; scaffold; synaptic function; transcription factor

DESCRIPTION (provided by applicant): mGluRs are G protein-coupled receptors enriched at excitatory synapses throughout the brain where they act both pre- and postsynaptically to regulate glutamatergic neurotransmission. Signaling by mGluRs is critical to synaptic circuitry formation during development and is implicated in forms of activity-dependent synaptic plasticity. Dysregulation of mGluR signaling is implicated in many neurological and psychiatric disorders linked to abnormal development, including Fragile X syndrome, the most common inherited form of mental retardation, epilepsy, schizophrenia, and addiction. The overall objective of this proposal is to understand the molecular mechanisms underlying the regulation of mGluR signaling by association with a key scaffolding protein in the brain. Preliminary evidence indicates that postsynaptic group I mGluRs (mGluR1/5) bind caveolin-1 and associate with membrane rafts. Caveolin-1, the main structural component of caveolae, acts as a molecular scaffold for a large number of signaling effector proteins and membrane receptors. Lipid rafts and caveolae are specialized membrane microdomains that serve as platforms to compartmentalize signaling activities at the cell surface. The hypothesis underlying the proposed studies is that association with caveolin-1 and membrane rafts regulates mGluR-dependent signal transduction. This proposal builds on our initial observations by pursuing the following Specific Aims: 1) Assess the role of caveolin-1 in the regulation of mGluR1/5-dependent changes in synapse composition. Experiments will examine the impact of caveolin-1 on 1) mGluR1/5-induced internalization of AMPA receptors; 2) mGluR1/5-induced local synthesis of proteins critical for synaptic plasticity; and 3) mGluR1/5-induced activation of transcription factors involved in memory storage. 2) Determine whether association with membrane rafts and caveolin-1 regulates mGluR signaling to effector proteins. Experiments will examine the association of mGluRs with signaling proteins in rafts vs. non-raft membrane domains and the role of caveolin-1 in regulating mGluR signaling to the PLC/InsP3/Ca2+ and ERK-MAPK pathways. Collectively, these studies will provide important insights not only into the regulation of mGluR signaling but also into mechanisms relevant to the establishment and maintenance of neuronal circuitry under physiological and pathological conditions, including inherited forms of mental retardation such as Fragile X syndrome. PUBLIC HEALTH RELEVANCE: mGluRs are G protein-coupled receptors enriched at excitatory synapses throughout the brain where they act both pre- and postsynaptically to regulate glutamatergic neurotransmission; signaling by mGluRs is critical to synaptic circuitry formation during development and is implicated in forms of activity-dependent synaptic plasticity. The overall objective of this proposal is to understand the molecular mechanisms underlying the regulation of mGluR signaling by association with a key scaffolding protein in the brain; these studies will provide insights into mechanisms relevant to the establishment and maintenance of neuronal circuitry under physiological and pathological conditions.

描述（由申请人提供）：mGluR 是 G 蛋白偶联受体，富含整个大脑的兴奋性突触，它们在突触前和突触后发挥作用，调节谷氨酸能神经传递。 mGluR 信号传导对于发育过程中突触回路的形成至关重要，并且与活动依赖性突触可塑性的形式有关。 mGluR 信号传导失调与许多与发育异常相关的神经和精神疾病有关，包括脆性 X 综合征（智力低下、癫痫、精神分裂症和成瘾的最常见遗传形式）。该提案的总体目标是了解 mGluR 信号传导通过与大脑中的关键支架蛋白关联进行调节的分子机制。初步证据表明，突触后 I 组 mGluR (mGluR1/5) 结合 Caveolin-1 并与膜筏相关。 Caveolin-1是小窝的主要结构成分，充当大量信号效应蛋白和膜受体的分子支架。脂筏和细胞膜穴是特殊的膜微域，充当划分细胞表面信号活动的平台。拟议研究的假设是，caveolin-1 和膜筏的关联调节 mGluR 依赖性信号转导。该提案建立在我们初步观察的基础上，追求以下具体目标：1) 评估 Caveolin-1 在调节 mGluR1/5 依赖性突触组成变化中的作用。实验将检查 Caveolin-1 对 1) mGluR1/5 诱导的 AMPA 受体内化的影响； 2) mGluR1/5诱导的对突触可塑性至关重要的蛋白质的局部合成； 3) mGluR1/5 诱导的参与记忆存储的转录因子的激活。 2) 确定与膜筏和 Caveolin-1 的关联是否调节 mGluR 信号传导至效应蛋白。实验将检查 mGluR 与筏膜域和非筏膜域中信号蛋白的关联，以及 Caveolin-1 在调节 PLC/InsP3/Ca2+ 和 ERK-MAPK 途径的 mGluR 信号传导中的作用。总的来说，这些研究不仅将为 mGluR 信号传导的调节提供重要的见解，而且还将为生理和病理条件下神经元回路的建立和维持相关的机制提供重要的见解，包括遗传性精神发育迟滞，例如脆性 X 综合征。公共健康相关性：mGluR 是 G 蛋白偶联受体，富含于整个大脑的兴奋性突触，它们在突触前和突触后发挥作用，调节谷氨酸能神经传递； mGluR 的信号传导对于发育过程中突触回路的形成至关重要，并且与活动依赖性突触可塑性的形式有关。该提案的总体目标是了解 mGluR 信号传导通过与大脑中的关键支架蛋白关联进行调节的分子机制；这些研究将深入了解生理和病理条件下神经元回路建立和维持的相关机制。