Metabotropic Glutamate Receptors in the Basal Ganglia

基底神经节的代谢型谷氨酸受体

• 批准号: 6936444
• 负责人: Yoland Smith
• 金额: $ 31.27万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-05-01 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936444
• 关键词: GABA receptor; Macaca mulatta; Parkinson' s disease; afferent nerve; basal ganglia; dopamine receptor; dopamine transporter; excitatory aminoacid; gene targeting; genetically modified animals; glutamate receptor; immunocytochemistry; laboratory mouse; nerve /myelin protein; neural transmission; protein binding; receptor expression; synapses

DESCRIPTION (provided by applicant): The trafficking and anchoring of neurotransmitter receptors to the neuronal plasma membrane are complex phenomena that involve specific interactions between the receptors and various scaffolding proteins. Over the past few years, the targeting of metabotropic glutamate receptors (mGluRs) has gained particular interest. The group I mGluRs, which comprises mGluR1 and mGluR5, are mostly expressed postsynaptically and produce slow depolarization through coupling with phospholipase C and IP3/Ca2+ receptors. Five years ago, Brakeman et al. (1997) identified a dendritic protein that selectively binds to group I mGluRs. The expression of this protein, which was named HOMER, appeared to be regulated by physiological synaptic activity and likely played a role in group I mGluRs signaling. Since then, 12 Homer cDNAs have been cloned. These cDNAs encode for various proteins with a similar structure named Homer 1a/b/c, Homer 2a/b and Homer 3. Although the exact functions of Homer in the brain remain to be established, various data, largely obtained in cultured cells, suggest that Homer is involved in the trafficking and synaptic targeting of group I mGluRs at specific sites along the neuronal plasma membrane. There is strong evidence that changes in dopamine transmission regulate Homer mRNA expression in the rat CNS. The lack of information on Homer proteins localization and their relationships with group I mGluRs hampers the progress of knowledge on Homer/mGluRs functional interactions in the CNS. During the first five years of this award, our laboratory studied in detail the subsynaptic and subcellular localization of group I mGluRs in the monkey basal ganglia. Two major findings stood out from these studies: (1) Group I mGluRs are expressed at both glutamatergic and non-glutamatergic synapses in various basal ganglia nuclei and (2) a large pool of mGluR5 is expressed intracellularly in basal ganglia output nuclei. These observations raised important questions regarding the functions, synaptic targeting, trafficking and regulation of group I mGluRs in the basal ganglia. In order to further characterize these issues and better understand the potential role(s) of Homer in basal ganglia functions, one of the objectives of this proposal is to elucidate the subcellular and subsynaptic relationships between Homer and group I mGluRs in the striatopallidal complex of monkeys. Another goal of this project is to characterize potential changes in the subcellular and subsynaptic localization of group I mGluRs in normal versus Homer knock out mice with or without lesion of midbrain dopaminergic neurons. Together, findings obtained in these studies will serve as a basic framework to understand Homer/mGluRs interactions in normal and pathological basal ganglia functions.

描述（由申请人提供）：神经递质受体在神经元质膜上的运输和锚定是复杂的现象，涉及受体与各种脚手架蛋白之间的特定相互作用。在过去的几年中，代谢型谷氨酸受体（MGLURS）的靶向引起了人们的特别关注。由MGLUR1和MGLUR5组成的I组MGlurs大多在突触后表达，并通过与磷脂酶C和IP3/CA2+受体偶联而产生缓慢的去极化。五年前，Brakeman等。 （1997）确定了一种与I组的树突状蛋白质。该蛋白质的表达被称为荷马，似乎受生理突触活性的调节，并可能在I组MGLURS信号传导中起作用。从那时起，已经克隆了12个本垒打cDNA。这些cDNA编码各种蛋白质，具有相似的结构，称为Homer 1A/B/C，Homer 2a/b和Homer 3。尽管荷马在大脑中的确切功能仍有待确定，但是在培养的细胞中大量获得的各种数据表明，荷马在特定网站沿Neurronal plas的I组的运输和突触靶向均参与了In neuronal plas的频繁范围。有强有力的证据表明，多巴胺传播的变化调节大鼠中枢神经系统中的荷马mRNA表达。缺乏有关荷马蛋白质本地化及其与I组的关系的信息阻碍了CNS中荷马/MGLURS功能相互作用的知识进步。在该奖项的前五年中，我们的实验室详细研究了猴子基底神经节中I组的突触和亚细胞定位。这些研究中有两个重大发现：（1）I组mglurs在各种基底神经节核中均表达在谷氨酸能和非谷氨酸助剂突触，并且（2）（2）大的mglur5池在基底神经节输出核中表达。这些观察结果提出了有关基础神经节中I组的功能，突触靶向，贩运和调节的重要问题。为了进一步表征这些问题，并更好地了解荷马在基底神经节功能中的潜在作用，该提案的目标之一是阐明猴子纹状体综合体中荷马和I群Mglurs之间的亚细胞和突触的关系。该项目的另一个目的是表征正常与荷马在荷马击倒中脑多​​巴胺能神经元的小鼠中I组的亚细胞和突触下的潜在变化。在这些研究中获得的发现将作为一个基本框架，以了解正常和病理基底神经节功能中的本垒打/mglurs相互作用。