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，在整个大脑中富含兴奋性突触前和突触后以调节谷氨酸能神经传递。 mglurs信号对发育过程中的突触回路形成，与活动依赖性突触形式有关可塑性。 MGLUR信号的失调与许多相关的神经系统和精神疾病有关对于异常发展，包括脆弱的X综合症，X综合症，这是最常见的心理遗传形式迟钝，癫痫，精神分裂症和成瘾。该提议的总体目的是了解通过与关键脚手架相关的调节MGLUR信号传导的分子机制大脑中的蛋白质。初步证据表明突触后I mglurs（mglur1/5）结合 caveolin-1并与膜筏搭配。 Caveolin-1是Caveolae的主要结构成分，充当用于大量信号效应蛋白和膜受体的分子支架。脂筏和 Caveolae是专门的膜微区细胞表面的活动。所提出的研究的基础假设是与小窝蛋白-1的关联膜筏调节MGlur依赖性信号转导。该提议建立在我们的最初通过追求以下特定目的观察：1）评估小窝林-1在调节中的作用 MGLUR1/5依赖性突触组成的变化。实验将检查Caveolin-1的影响在1）MGLUR1/5诱导的AMPA受体的内在化； 2）MGLUR1/5诱导的蛋白质局部合成对于突触可塑性至关重要； 3）MGLUR1/5诱导的记忆中涉及转录因子的激活贮存。 2）确定与膜筏和小窝蛋白1是否相关向效应蛋白发出信号。实验将检查mglurs与信号蛋白的关联筏与非羊膜结构域以及小窝蛋白-1在调节mglur信号中的作用 PLC/INSP3/Ca2+和ERK-MAPK途径。总的来说，这些研究将不仅提供重要见解纳入MGLUR信号的调节，也可以参与与机构相关的机制在生理和病理条件下维持神经元电路，包括遗传形式智力障碍，例如脆弱的X综合征。