FUNCTIONS OF METABOTROPIC GLUTAMATE RECEPTOR SUBTYPES

代谢型谷氨酸受体亚型的功能

• 批准号: 2891858
• 负责人: P Jeffrey Conn
• 金额: $ 25.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2891858
• 关键词: adenylate cyclase; autocrine; enzyme activity; glutamate receptor; granule cell; hippocampus; immunocytochemistry; immunoelectron microscopy; laboratory rabbit; laboratory rat; neural transmission; neuropharmacology; oligopeptides; pyramidal cells; receptor coupling; synapses; voltage /patch clamp

The hippocampus plays an important role in a number of normal physiological processes and in pathological conditions, including Alzheimer's disease and epilepsy. Development of a complete understanding of the molecular and cellular mechanisms of regulation of synaptic function in the hippocampus could lead to new strategies for treatment of these disorders. Until recently, it was thought that all of the actions of glutamate, the major excitatory neurotransmitter in the hippocampus, were mediated by activation of ligand-gated cation channels. However, it is now clear that glutamate also activates metabotropic glutamate receptors (mGluRs), that are coupled to effector systems through GTP binding proteins. mGluRs play a number of important roles in regulating cell excitability and synaptic transmission in the hippocampus. However, the precise physiological roles of the different mGluR subtypes are not known. A complete understanding of both normal and pathological hippocampal function will require a detailed understanding of the roles of mGluRs in regulating hippocampal physiology. Eight mGluR subtypes have been cloned and these receptors have been classified into three major groups. Many of the physiolological roles of group I mGluRs (mGluR1 and mGluR5) in the hippocampus have been defined, but less is known about the physiological roles of the group II (mGluR2 and mGluR3) and group III (mGluRs 4, 6, 7, and 8) mGluRs. A series of studies is proposed that is aimed at determining the localization and physiological roles of group II and group III mGluRs in the hippocampus and the cellular mechanisms by which activation of these receptors modulates hippocampal function. Patch clamp recordings in hippocampal slices and studies of mGluR pharmacology in expression systems will be used to test the hypothesis that a group II mGluR serves as an autoreceptor at the perforant path synapses. mGluR2 and mGluR3-specific antibodies will then be used for immunocytochemistry with electron microscopy (immuno-EM) to definitively determine whether mGluR2 and/or mGluR3 is presynaptically localized at these synapses. Immuno-EM will then be used to test the hypothesis that mGluR4a is localized postsynaptically and mGluR7 presynaptically on hippocampal neurons. Patch clamp recordings in hippocampal slices and studies of mGluR4a and mGluR7 pharmacology in expression systems will then be used to test the hypothesis that these receptors play distinct pre- and postsynaptic roles in the hippocampus. In addition to advancing our knowledge of hippocampal function, these studies will lead to a more complete understanding of the physiology and pharmacology of the mGluR family. Glutamate is the major excitatory neurotransmitter in the central nervous system and glutamatergic synapses are widespread throughout the brain. Thus, the mGluRs are likely to play important roles in various aspects of brain function. Developing an understanding of the physiological roles of each mGluR subtype will ultimately lead to advances in a number of areas of neurobiology.

海马体在许多正常的 生理过程和病理情况，包括 阿尔茨海默氏症和癫痫。发展一种完整的理解 突触调控的分子和细胞机制 海马体的功能可能会导致新的治疗策略 这些障碍。直到最近，人们还认为美国政府的所有行动 谷氨酸是海马区的主要兴奋性神经递质， 通过激活配基门控阳离子通道来调节。然而，现在是 明确谷氨酸也能激活代谢型谷氨酸受体 (MGluRs)，通过GTP结合与效应器系统偶联 蛋白质。MGluRs在细胞调节中发挥着许多重要作用 海马区的兴奋性和突触传递。然而， 不同mGluR亚型的确切生理作用尚不清楚。 对正常和病理性海马区的全面了解 功能将需要详细了解mGluRs在 调节海马区生理。已克隆了8个mGluR亚型 这些受体被分为三大类。许多. I型mGluRs(mGluR1和mGluR5)在脑出血中的生理作用 海马体已经被定义，但对生理学知识知之甚少 第二组(mGluR2和mGluR3)和第三组(mGluR4，6，7， (8)mGluRs。提出了一系列的研究，旨在 确定第二组和第二组的定位和生理作用 III海马区mGluRs及其细胞机制 这些受体的激活调节了海马体的功能。膜片钳 大鼠海马片记录及mGluR药理研究 表达系统将被用来检验第二组的假设 MGluR作为穿支通路突触的自身受体。MGluR2和 MGluR3特异性抗体随后将用于免疫细胞化学 电子显微镜(免疫-EM)确定mGluR2 和/或mGluR3在突触前定位于这些突触。免疫-EM 然后用来检验mGluR4a被本地化的假设 突触后和突触前mGluR7表达于海马神经元。补片 海马片钳夹记录及mGluR4a和mGluR7的研究 然后将使用表达系统中的药理学来测试 假设这些受体在突触前和突触后发挥不同的作用 在海马体中。除了提高我们对海马体的认识 功能，这些研究将导致对更完整的理解 MGluR家族的生理学和药理学。谷氨酸是主要的 中枢神经系统中的兴奋性神经递质 谷氨酸能突触广泛存在于大脑各处。因此， MGluRs可能在大脑的各个方面发挥重要作用 功能。发展对每一个人的生理作用的理解 MGluR亚型最终将在以下几个领域取得进展 神经生物学。