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

• 批准号: 7871511
• 负责人: ANNA FRANCESCONI
• 金额: $ 41.5万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7871511
• 关键词: AMPA Receptors; Adaptor Signaling Protein; Adenylate Cyclase; Alzheimer' 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; Maintenance; Membrane; Membrane Microdomains; Membrane Proteins; Memory; Mental Retardation; Mental disorders; Metabotropic Glutamate Receptors; Modification; Molecular; Morphology; Neurologic; Neurons; Parkinson Disease; Pathway interactions; Phospholipase C; Physiological; Play; Protein Biosynthesis; 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; neural circuit; neuronal circuitry; neuropsychiatry; neurotransmission; neurotransmitter release; postsynaptic; presynaptic; public health relevance; receptor; research study; scaffold; synaptic function; transcription factor

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.

描述（由申请人提供）：mglurs是G蛋白偶联受体，富含整个大脑的兴奋性突触，它们在突触前和突触后起作用以调节谷氨酸能神经传递。 mglurs信号对于发育过程中的突触回路形成至关重要，并且与活动依赖性突触可塑性的形式有关。 MGLUR信号传导的失调与许多与异常发育有关的神经系统和精神疾病涉及，包括脆弱的X综合征，X综合征是智力低下的最常见的遗传性形式，癫痫，精神分裂症和成瘾。该提案的总体目的是了解通过与大脑中的关键脚手架蛋白相关的MGLUR信号传导的分子机制。初步证据表明，突触后I mglurs（MGLUR1/5）结合了小窝蛋白1，并与膜筏缔合。 Caveolin-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。脂质筏和小窝是专门的膜微区，可作为细胞表面信号活性的平台。所提出的研究的基本假设是，与小窝蛋白-1和膜筏的关联调节MGLUR依赖性信号转导。该提案通过追求以下特定目的来建立我们的最初观察结果：1）评估小窝蛋白-1在MGLUR1/5依赖于突触组成的变化中的作用。实验将检查Caveolin-1对1）MGLUR1/5诱导的AMPA受体内在化的影响； 2）MGLUR1/5诱导的局部合成对突触可塑性至关重要的蛋白质； 3）MGLUR1/5诱导的记忆存储中涉及的转录因子的激活。 2）确定与膜筏和小窝蛋白-1是否关联是否调节效应蛋白的mglur信号传导。实验将检查MGLURS与筏中的信号蛋白与非吊膜结构域的关联，以及Caveolin-1在调节MGLUR信号与PLC/INSP3/CA2+和ERK-MAPK途径中的作用。总的来说，这些研究将不仅为MGLUR信号的调节提供重要的见解，还将为与生理和病理条件下的神经元电路的建立和维持相关的机制提供了重要的见解，包括遗传性智力低下的形式，例如脆弱的X综合征。公共卫生相关性：mglurs是G蛋白偶联受体，在整个大脑的兴奋性突触中富含蛋白质偶联的受体，在这些突触中，它们在突触前和突触后的作用以调节谷氨酸能神经传递； mglurs信号对于发育过程中的突触回路形成至关重要，并且与活动依赖性突触可塑性的形式有关。该提案的总体目的是了解通过与大脑中的关键脚手架蛋白相关的MGLUR信号传导的分子机制。这些研究将提供有关与生理和病理条件下神经元电路相关的机制的见解。