Regulation of Metabotropic glutamate Receptor Signaling by Caveolar Rafts

描述（由申请人提供）：mGluR是在整个大脑的兴奋性突触处富集的G蛋白偶联受体，它们在突触前和突触后均起作用以调节突触能神经传递。通过mGluRs的信号传导对于发育期间的突触回路形成至关重要，并且涉及活性依赖性突触可塑性的形式。mGluR信号传导的失调涉及与异常发育相关的许多神经和精神疾病，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。这项建议的总体目标是了解潜在的调节mGluR信号的分子机制与大脑中的关键支架蛋白。初步证据表明，突触后I组mGluR（mGluR 1/5）结合小窝蛋白-1和与膜筏。Caveolin-1是细胞膜小窝的主要结构成分，是众多信号效应蛋白和膜受体的分子支架。脂筏和小窝是专门的膜微区，作为平台，在细胞表面区隔信号活动。所提出的研究的假设是，与小窝蛋白-1和膜筏调节mGluR依赖的信号转导。本研究基于我们的初步观察结果，具体目标如下：1）评估小窝蛋白-1在调节突触组成中mGluR 1/5依赖性变化中的作用。实验将检查小窝蛋白-1对1）mGluR 1/5诱导的AMPA受体内化; 2）mGluR 1/5诱导的对突触可塑性至关重要的蛋白质的局部合成;和3）mGluR 1/5诱导的参与记忆储存的转录因子的激活的影响。2)确定是否与膜筏和小窝蛋白-1调节mGluR信号转导效应蛋白。实验将检查mGluR与筏与非筏膜结构域中的信号蛋白的关联，以及小窝蛋白-1在调节mGluR信号传导至PLC/InsP 3/Ca 2+和ERK-MAPK通路中的作用。总的来说，这些研究将提供重要的见解，不仅到调节mGluR信号，但也到相关的机制，建立和维护神经元回路的生理和病理条件下，包括遗传形式的精神发育迟滞，如脆性X综合征。公共卫生相关性：mGluR是在整个大脑的兴奋性突触处富集的G蛋白偶联受体，其中它们在突触前和突触后作用以调节突触能神经传递; mGluR的信号传导对于发育期间的突触回路形成至关重要，并且涉及活性依赖性突触可塑性的形式。该提案的总体目标是了解与大脑中的关键支架蛋白相关的mGluR信号调节的分子机制;这些研究将为生理和病理条件下神经元回路的建立和维持相关机制提供见解。

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.