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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

基本信息

批准号：
8442915
负责人：
ANNA FRANCESCONI
金额：
$ 39.44万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8442915
关键词：
AMPA Receptors Adaptor Signaling Protein Adenylate Cyclase Alzheimer&apos 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 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

项目摘要

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.

mGluRs是G蛋白偶联受体，富集在整个大脑的兴奋性突触中，在那里它们起作用在突触前和突触后调节突触能神经传递。mGluRs的信号传导对于在发育过程中形成突触回路，并与活动依赖性突触形式有关。可塑性mGluR信号转导失调与许多神经和精神疾病有关，发育异常，包括脆性X综合征，最常见的遗传性精神疾病发育迟缓、癫痫、精神分裂症和成瘾。本提案的总体目标是了解与关键支架相关的mGluR信号调节的分子机制大脑中的蛋白质。初步证据表明，突触后I组mGluR（mGluR 1/5）结合 caveolin-1与膜筏相关。小窝蛋白-1是小窝的主要结构成分，大量信号效应蛋白和膜受体的分子支架。脂质筏和小窝是专门的膜微区，作为平台，细胞表面的活动。这项研究的假设是，与小窝蛋白-1相关的膜筏调节mGluR依赖的信号转导。该提案建立在我们最初的通过追求以下具体目标观察：1）评估小窝蛋白-1在调节 mGluR 1/5依赖性突触组成的变化。实验将检验小窝蛋白-1的影响 1）mGluR 1/5诱导的AMPA受体内化; 2）mGluR 1/5诱导的蛋白质局部合成突触可塑性的关键; 3）mGluR 1/5诱导的参与记忆的转录因子的激活存储. 2)确定与膜筏和小窝蛋白-1的结合是否调节mGluR 信号传导至效应蛋白。实验将检查mGluRs与细胞中信号蛋白的关联，筏与非筏膜结构域和小窝蛋白-1在调节mGluR信号转导中的作用 PLC/InsP 3/Ca 2+和ERK-MAPK通路。总的来说，这些研究将提供重要的见解，不仅调节mGluR信号传导，而且还与建立和在生理和病理条件下维持神经元回路，包括遗传形式的精神发育迟滞，如脆性X综合征。