The Role of Intracellular Metabotropic Glutamate Receptor 5 at the Synapse

细胞内代谢型谷氨酸受体 5 在突触中的作用

• 批准号: 8002426
• 负责人: Carolyn Ann Purgert
• 金额: $ 2.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8002426
• 关键词: AMPA Receptors; Agonist; Anxiety; Area; Autistic Disorder; Calcium; Cell Surface Receptors; Cell membrane; Cell surface; Clinical Trials; Corpus striatum structure; Coupling; Disease; Drug Delivery Systems; Endocytosis; Endoplasmic Reticulum; Fragile X Mental Retardation Protein; Fragile X Syndrome; Functional disorder; G-Protein-Coupled Receptors; Genes; Genetic Transcription; Glutamate Receptor; Glutamates; Goals; Hippocampus (Brain); Incidence; Knowledge; Lead; Learning; Ligands; Memory; Memory Disorders; Mental Retardation; Neurologic; Neurons; Nuclear Envelope; Pathway interactions; Physiological; Play; Protein Biosynthesis; Public Health; Receptor Cell; Research; Role; Seizures; Signal Transduction; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Trinucleotide Repeat Expansion; addiction; autism spectrum disorder; improved; metabotropic glutamate receptor 5; public health relevance; receptor; receptor internalization; response

DESCRIPTION (provided by applicant): The Role of Intracellular Metabotropic Glutamate Receptor 5 at the Synapse Project Summary By coupling to various intracellular cascades, metabotropic glutamate receptor 5 (mGluR5) plays an important role throughout the CNS in modulating neuronal activity and synaptic transmission. Dysfunction of mGluR5 is implicated in a variety of neurological problems including anxiety, seizures, addiction, learning and memory disorders, and Fragile X Syndrome (FXS). In FXS, a single-gene disorder characterized by mental retardation and a range of autistic features, an expanded trinucleotide repeat results in a deficiency of Fragile X Mental Retardation Protein (FMRP). FMRP normally acts as a translational repressor to oppose mGluR5 signaling; thus, the lack of FMRP in FXS leads to overactivity of mGluR5. To correct the excess mGluR5 activity, mGluR5 antagonists are currently undergoing clinical trials as a treatment for FXS. Although G-protein coupled receptors like mGluR5 are traditionally thought to initiate their signaling cascades from the cell surface, there is mounting evidence that intracellular receptors, located on the nuclear membrane and endoplasmic reticulum, are also physiologically significant. Notably, up to 90% of mGluR5 is intracellularly located, where it gives rise to unique calcium responses and downstream signaling cascades in dissociated striatal cultures. The native ligand of mGluR5, glutamate, can cross the cell membrane via various transporters and exchangers; therefore, glutamate released at a synapse can activate both cell surface mGluR5 as well as intracellular mGluR5. The downstream pathways initiated by mGluR5 activation lead to local protein synthesis at the synapse and AMPA receptor (an excitatory ionotropic glutamate receptor) endocytosis as well as transcription of synaptic plasticity genes; however, the contributions of cell surface mGluR5 versus intracellular mGluR5 are not yet well-established. The goal of this proposal is to test the hypothesis that activation of intracellular mGluR5 versus cell surface mGluR5 has differential effects on protein synthesis and AMPA receptor internalization in the hippocampus. The hippocampus is an appropriate area on which to focus due to its importance in learning and memory and its established responses to cell surface mGluR5 activation by the impermeable mGluR5 agonist, DHPG. Using sets of permeable and impermeable mGluR5 agonists and antagonists, activation of intracellular mGluR5 or cell surface mGluR5 can be achieved in isolation in order to delineate their downstream effects; for instance, intracellular receptors alone can be activated with application of a permeable agonist and an impermeable antagonist. Defining the role of intracellular mGluR5 activation is important both conceptually, in showing the physiological relevance of intracellular G-protein coupled receptors, and clinically, in targeting drugs to intracellular receptors, cell surface receptors, or both. For Fragile X Syndrome and possibly autism, understanding the role of intracellular mGluR5 will be crucial in developing suitable mGluR5 antagonists for therapeutic treatments. PUBLIC HEALTH RELEVANCE: This project will benefit public health in the search for appropriate treatments for Fragile X Syndrome by improving our understanding of the underlying mechanisms of this disorder. This research will help clarify the function of a receptor known to be involved in Fragile X Syndrome. The knowledge gained from these studies may be applicable to autism spectrum disorders as well, which would have a major impact on public health given the recent increase in incidence of autism.

描述（由申请人提供）： 细胞内代谢型谷氨酸受体5（mGluR 5）通过与各种细胞内级联反应偶联，在整个中枢神经系统中调节神经元活动和突触传递中发挥重要作用。mGluR 5的功能障碍涉及多种神经问题，包括焦虑、癫痫发作、成瘾、学习和记忆障碍以及脆性X综合征（FXS）。FXS是一种以智力迟钝和一系列自闭症特征为特征的单基因疾病，在FXS中，扩展的三核苷酸重复序列导致脆性X智力迟钝蛋白（FMRP）缺乏。FMRP通常作为翻译阻遏物来对抗mGluR 5信号传导;因此，FXS中FMRP的缺乏导致mGluR 5的过度活性。为了纠正过量的mGluR 5活性，mGluR 5拮抗剂目前正在进行临床试验作为FXS的治疗。 虽然传统上认为G蛋白偶联受体如mGluR 5从细胞表面启动其信号级联，但越来越多的证据表明位于核膜和内质网上的细胞内受体也具有生理学意义。值得注意的是，高达90%的mGluR 5位于细胞内，在分离的纹状体培养物中，它引起独特的钙反应和下游信号级联。mGluR 5的天然配体谷氨酸可以通过各种转运蛋白和交换剂穿过细胞膜;因此，在突触处释放的谷氨酸可以激活细胞表面mGluR 5以及细胞内mGluR 5。由mGluR 5激活启动的下游途径导致突触和AMPA受体（一种兴奋性离子型谷氨酸受体）内吞作用的局部蛋白质合成以及突触可塑性基因的转录;然而，细胞表面mGluR 5与细胞内mGluR 5的贡献尚未完全确定。 该提议的目的是检验细胞内mGluR 5与细胞表面mGluR 5的激活对海马中蛋白质合成和AMPA受体内化具有不同影响的假设。海马是一个适当的区域，重点是由于其在学习和记忆中的重要性，其建立的细胞表面mGluR 5激活的不可渗透的mGluR 5激动剂，DHPG的反应。使用可渗透和不可渗透的mGluR 5激动剂和拮抗剂组，可以单独实现细胞内mGluR 5或细胞表面mGluR 5的激活，以描述其下游效应;例如，可以通过应用可渗透激动剂和不可渗透拮抗剂来激活单独的细胞内受体。定义细胞内mGluR 5激活的作用在概念上（在显示细胞内G蛋白偶联受体的生理相关性方面）和临床上（在将药物靶向细胞内受体、细胞表面受体或两者方面）都是重要的。对于脆性X综合征和可能的自闭症，了解细胞内mGluR 5的作用将是至关重要的，在开发合适的mGluR 5拮抗剂的治疗性治疗。 公共卫生关系： 该项目将有利于公共卫生，通过提高我们对这种疾病的潜在机制的理解，寻找脆性X综合征的适当治疗方法。这项研究将有助于阐明已知参与脆性X综合征的受体的功能。从这些研究中获得的知识可能也适用于自闭症谱系障碍，鉴于最近自闭症发病率的增加，这将对公共卫生产生重大影响。