FUNCTIONS OF METABOTROPIC GLUTAMATE RECEPTOR SUBTYPES

代谢型谷氨酸受体亚型的功能

• 批准号: 2269298
• 负责人: P Jeffrey Conn
• 金额: $ 13.87万
• 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 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2269298
• 关键词: CHO cells; adenylate cyclase; antireceptor antibody; dentate gyrus; entorhinal cortex; enzyme activity; epitope mapping; excitatory aminoacid; glutamate receptor; granule cell; immunocytochemistry; interneurons; isoproterenol; laboratory rabbit; laboratory rat; lipolysis; membrane potentials; neural inhibition; neurotransmitter transport; oligopeptides; phosphatidylcholines; 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 most neuro- modulatory influences on hippocampal function required activation of extrinsic afferents and that all of the actions of glutamate, the major neurotransmitter intrinsic to the hippocampus, were mediated by activation of ligandgated cation channels. However, it is now clear that glutamate also activates receptors, known as metabotropic glutamate receptors (mGluRs), that are coupled to effector systems through GTP binding proteins. To date, 5 mGluR subtypes have been cloned. However, the precise roles of the different mGluR subtypes in regulating neuronal excitability and synaptic transmission in the hippocampus 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. Interestingly, application of IS,3R- ACPD (a selective mGluR agonist) to hippocampal slices, potentiates cyclic AMP responses to agonists of other receptors that are positively coupled to adenylate cyclase. Also, IS,3R-ACPD has a number of important physiological effects in the hippocampus. These include, among others, a decrease in synaptic -inhibition in hippocampal area CA1 and a decrease in evoked population spikes in the dentate gyrus. However, the precise cellular and synaptic mechanisms by which mGluR agonists modulate inhibitory and excitatory synaptic responses in the hippocampus are not known. Furthermore, the physiological relevance of 1S,3R-ACPD-induced potentiation of cyclic AMP responses is not known. A series of experiments is proposed in which microelectrode and patch clamp recordings from hippocampal neurons will be used to test the hypothesis that 1S,3R-ACPD decreases synaptic inhibition in area CA1 and evoked population spikes in dentate gyrus by reducing excitatory transmission onto inhibitory interneurons and dentate granule cells, respectively. Also, experiments will be performed to determine the physiological role of mGluR-mediated potentiation of cyclic AMP responses in regulating synaptic transmission in the hippocampus. Finally, specific antibodies will be raised against each of the cloned mGluR subtypes. These will be used to determine the precise cellular and subcellular localization of the different mGluR subtypes in the hippocampal formation. These studies, coupled with the electrophysiological experiments, will provide valuable information regarding the roles of specific mGluR subtypes in regulating hippocampal function.

海马体在许多正常生理活动中发挥着重要作用 生理过程和病理条件，包括 阿尔茨海默病和癫痫症。形成完整的理解 突触调节的分子和细胞机制 海马体的功能可能会带来新的治疗策略 这些疾病。 直到最近，人们还认为大多数神经 对海马功能的调节影响需要激活 外在传入和谷氨酸的所有作用，主要 海马体固有的神经递质，由 配体门控阳离子通道的激活。 然而，现在很清楚的是 谷氨酸还激活受体，称为代谢型谷氨酸 受体 (mGluR)，通过 GTP 与效应系统耦合 结合蛋白。迄今为止，已克隆了 5 个 mGluR 亚型。然而， 不同 mGluR 亚型在调节神经元中的精确作用 海马体的兴奋性和突触传递尚不清楚。 对正常和病理海马的完整了解 功能需要详细了解 mGluRs 在 调节海马生理。有趣的是，IS，3R-的应用 ACPD（一种选择性 mGluR 激动剂）作用于海马切片，增强 环AMP对其他受体激动剂的反应呈阳性 与腺苷酸环化酶偶联。此外，IS,3R-ACPD 有许多重要的 海马体的生理效应。其中包括，除其他外， 海马 CA1 区突触抑制减少 齿状回的诱发群体峰值。然而，准确的 mGluR 激动剂调节的细胞和突触机制 海马体的抑制性和兴奋性突触反应不 已知。此外，1S,3R-ACPD 诱导的生理相关性 环 AMP 反应的增强作用尚不清楚。一系列 提出了实验，其中微电极和膜片钳 海马神经元的记录将用于检验假设 1S,3R-ACPD 降低 CA1 区突触抑制并诱发 通过减少兴奋性传递，齿状回的数量激增 分别作用于抑制性中间神经元和齿状颗粒细胞。 此外，还将进行实验以确定其生理作用 mGluR介导的环AMP反应增强在调节中的作用 海马体中的突触传递。 最后是特异性抗体 将针对每个克隆的 mGluR 亚型产生。这些将是 用于确定精确的细胞和亚细胞定位 海马结构中不同的 mGluR 亚型。 这些 研究与电生理学实验相结合，将提供 有关特定 mGluR 亚型在 调节海马功能。