Regulation of Metabotropic glutamate Receptor Signaling by Caveolar Rafts

描述(申请人提供)：mGluRs是G蛋白偶联受体，丰富在整个大脑的兴奋性突触，在那里它们在突触前和突触后发挥作用，调节谷氨酸能神经传递。MGluRs信号在发育过程中对突触回路的形成至关重要，并与多种形式的活性依赖的突触可塑性有关。MGluR信号的失调与许多与发育异常有关的神经和精神疾病有关，包括脆性X综合征，最常见的遗传性智力低下形式，癫痫，精神分裂症和成瘾。这项建议的总体目标是通过与大脑中的一个关键支架蛋白相关联来了解mGluR信号调节的分子机制。初步研究表明，突触后I组mGluRs(mGluR1/5)与小窝蛋白-1结合，并与膜筏结合。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。脂筏和小窝是特殊的膜微域，作为划分细胞表面信号活动的平台。提出的研究假设是，与小窝蛋白-1和膜筏的关联调节mGluR依赖的信号转导。这个建议建立在我们最初的观察基础上，追求以下具体目标：1)评估小窝蛋白-1在调节依赖mGluR1/5的突触组成变化中的作用。实验将检测小窝蛋白-1对1)mGluR1/5诱导的AMPA受体内化；2)mGluR1/5诱导突触可塑性关键蛋白质的局部合成；以及3)mGluR1/5诱导参与记忆存储的转录因子的激活的影响。2)确定膜筏和小窝蛋白-1的结合是否调节mGluR信号转导效应蛋白。实验将研究mGluR与RAFT和非RAFT膜结构域中信号蛋白的联系，以及小窝蛋白-1在调节mGluR信号到PLC/InsP3/Ca~(2+)和ERK-MAPK通路中的作用。总之，这些研究不仅将为mGluR信号的调控提供重要的见解，还将为在生理和病理条件下建立和维持神经元回路相关的机制提供重要的见解，包括遗传性智力低下，如脆性X综合征。与公共健康相关：mGluRs是一种G蛋白偶联受体，在整个大脑的兴奋性突触中丰富，在突触前和突触后发挥作用，调节谷氨酸能神经传递；mGluRs发出的信号对发育过程中突触电路的形成至关重要，并与活性依赖的突触可塑性有关。这项建议的总体目标是通过与大脑中的关键支架蛋白相关联来了解mGluR信号调节的分子机制；这些研究将为在生理和病理条件下建立和维持神经元电路的相关机制提供见解。

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.