FUNCTIONS OF METABOTROPIC GLUTAMATE RECEPTOR SUBTYPES

代谢型谷氨酸受体亚型的功能

• 批准号: 2460550
• 负责人: P Jeffrey Conn
• 金额: $ 23.63万
• 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/2460550
• 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 生理过程和病理条件，包括 老年痴呆症和癫痫。全面理解的发展 突触调节的分子和细胞机制 海马体的功能可能会导致新的治疗策略， 这些紊乱。直到最近，人们还认为， 谷氨酸是海马体中主要的兴奋性神经递质， 通过激活配体门控阳离子通道介导。但现在 谷氨酸也激活代谢型谷氨酸受体 （mGluRs），其通过GTP结合与效应子系统偶联 proteins. mGluRs在调节细胞凋亡中起重要作用， 兴奋性和海马体中的突触传递。但 不同mGluR亚型的精确生理作用尚不清楚。 完整了解正常和病理海马 功能将需要详细了解mGluRs的作用， 调节海马体的生理机能已克隆了八种mGluR亚型 这些受体被分为三大类。许多 I组mGluR（mGluR 1和mGluR 5）在糖尿病中的生理作用 海马已经被定义，但对海马的生理功能知之甚少。 组II（mGluR 2和mGluR 3）和组III（mGluR 4，6，7， 和8）mGluRs。提出了一系列研究，旨在 确定II组和II组的定位和生理作用， III海马中的mGluRs和细胞机制， 这些受体的激活调节海马的功能。膜片钳 海马切片中的记录和研究mGluR药理学， 表达系统将被用来测试的假设，第二组 mGluR在穿通通路突触处充当自身受体。mglur 2和 然后将mGluR 3特异性抗体用于免疫细胞化学， 电子显微镜（免疫EM），以明确确定是否mGluR 2 和/或mGluR 3在突触前定位于这些突触。免疫电镜 然后将用于检验mGluR 4a定位于 突触后和mGluR 7突触前对海马神经元的影响。 贴片 海马脑片钳夹记录及mGluR 4a和mGluR 7的研究 表达系统中的药理学将用于测试 这些受体在突触前和突触后发挥不同作用的假说 在海马区。除了提高我们对海马的认识， 功能，这些研究将导致更全面的了解 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， 神经元突触遍布整个大脑。因此 mGluRs可能在脑的各个方面发挥重要作用 功能 发展对每一种生理作用的理解 mGluR亚型将最终导致在一些领域的进展， 神经生物学