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）：mGluRs是在整个大脑的兴奋性突触富集的G蛋白偶联受体，它们在突触前和突触后都起作用，调节谷氨酸能神经传递。mGluRs的信号传导对发育过程中突触回路的形成至关重要，并与活动依赖性突触可塑性的形式有关。mGluR信号的失调与许多与异常发育相关的神经和精神疾病有关，包括脆性X综合征，最常见的遗传形式的智力迟钝，癫痫，精神分裂症和成瘾。本提案的总体目标是了解mGluR信号通过与大脑中关键支架蛋白相关而调控的分子机制。初步证据表明，突触后I组mGluRs （mGluR1/5）结合caveolin-1并与膜筏相关。小窝蛋白-1是小窝的主要结构成分，是大量信号效应蛋白和膜受体的分子支架。脂筏和小泡是一种特殊的膜微结构域，可作为细胞表面信号活动区隔的平台。所提出的研究的假设是，与小泡蛋白-1和膜筏的关联调节mglur依赖的信号转导。该建议建立在我们最初的观察基础上，通过追求以下具体目标：1)评估caveolin-1在调节mglur1 /5依赖性突触组成变化中的作用。实验将检测caveolin-1对1)mglur1 /5诱导的AMPA受体内化的影响；2) mglur1 /5诱导突触可塑性关键蛋白的局部合成；3) mglur1 /5诱导的记忆存储相关转录因子的激活。2)确定与膜筏和caveolin-1的关联是否调节mGluR向效应蛋白的信号传导。实验将研究mGluR与筏膜和非筏膜结构域信号蛋白的关联，以及caveolin-1在调节mGluR信号传导至PLC/InsP3/Ca2+和ERK-MAPK通路中的作用。总的来说，这些研究不仅将为mGluR信号的调控提供重要的见解，而且还将为生理和病理条件下神经回路的建立和维持提供相关的机制，包括遗传性智力迟钝，如脆性X综合征。公共卫生相关性：mGluRs是在整个大脑兴奋性突触富集的G蛋白偶联受体，它们在突触前和突触后都起作用，调节谷氨酸能神经传递；mGluRs的信号传导对发育过程中突触回路的形成至关重要，并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信号通过与大脑中关键支架蛋白相关而调控的分子机制；这些研究将为在生理和病理条件下神经元回路的建立和维持提供相关的机制。