Regulation of Metabotropic glutamate Receptor Signaling by Caveolar Rafts

MGluR是一种G蛋白偶联受体，在整个大脑中的兴奋性突触中丰富，它们在那里起作用 在突触前和突触后调节谷氨酸能神经传递。MGluRs的信号转导对于 突触回路在发育过程中的形成，并与活动依赖型突触的形式有关 可塑性。MGluR信号调节失调与许多神经和精神疾病有关 到发育异常，包括脆性X综合征，这是最常见的精神遗传性形式 发育迟缓、癫痫、精神分裂症和成瘾。这项建议的总体目标是了解 关键支架参与mGluR信号调控的分子机制 大脑中的蛋白质。初步证据表明，突触后I组mGluRs(mGluR1/5)与 Caveolin-1，并与膜筏结合。小窝的主要结构成分Caveolin-1具有以下作用 大量信号效应蛋白和膜受体的分子支架。脂筏和 小窝是专门的膜微域，作为划分信号的平台 细胞表面的活动。支持这项研究的假设是，与小窝蛋白-1 膜筏调控mGluR依赖的信号转导。这项建议建立在我们最初的基础上 通过追求以下具体目标进行观察：1)评估小窝蛋白-1在调节 突触成分中依赖mGluR1/5的变化。实验将检验小窝蛋白-1的影响 1)mGluR1/5诱导AMPA受体内化；2)mGluR1/5诱导蛋白质局部合成 突触可塑性的关键；以及3)mGluR1/5诱导的涉及记忆的转录因子的激活 储藏室。2)确定与膜筏和小窝蛋白-1的结合是否调节mGluR 向效应器蛋白发送信号。实验将检查mGluR与信号蛋白在 RAFT与非RAFT膜结构域的比较以及小窝蛋白-1在调节mGluR信号通路中的作用 PLC/InsP3/Ca~(2+)和ERK-MAPK信号通路。总的来说，这些研究不仅将提供重要的见解 研究mGluR信号的调节，也研究与建立和 在生理和病理条件下维持神经元回路，包括遗传性 智力低下，如脆性X综合征。

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.