FUNCTIONS OF METABOTROPIC GLUTAMATE RECEPTOR SUBTYPES

代谢型谷氨酸受体亚型的功能

• 批准号: 6393608
• 负责人: P Jeffrey Conn
• 金额: $ 34.22万
• 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 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393608
• 关键词: enzyme activity; glutamate receptor; guanine nucleotide binding protein; hippocampus; immunocytochemistry; laboratory rabbit; laboratory rat; neuropharmacology; neurotransmitter transport; phosphorylation; protein isoforms; protein kinase C; protein localization; receptor coupling; voltage /patch clamp

The hippocampus plays an important role in a number of normal physiological processes and in a variety of pathological conditions, including Alzheimer's disease and temporal lobe epilepsy. Development of a complete understanding of the molecular and cellular mechanisms involved in regulation of hippocampal function 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. A complete understanding of both normal and pathological hippocampal function will require a detailed understanding of the roles of mGluRs in modulating hippocampal physiology and the molecular mechanisms involved in regulating signaling by members of this important receptor family. Eight m(GluR subtypes (mGluR1 - mGluR8) have been identified by molecular cloning. In the hippocampus, evidence suggests that m(GluR2, mGluR7 and mGluR8 are all localized on presynaptic glutamatergic nerve terminals where they may serve to inhibit glutamate release. However, the postulated roles of mGluR7 and mGluR8 in regulating transmission at specific hippocampal synapses have not been definitively established. We recently reported that mGluR- mediated regulation of glutamate release can be inhibited by activation of protein kinase C (PKC). However, at present, the mechanism by which PKC inhibits signaling by presynaptic mGluRs is not known. A series of studies is proposed in which a combination of anatomical, pharmacological, and genetic approaches will be used to rigorously test the hypothesis that mGluR7 and m(GluR8 serve as presynaptic receptors at two major hippocampal synapses. We will then employ biochemical, electrophysiological, and molecular approaches to rigorously test the hypothesis that activation of PKC inhibits the function of presynaptic mGluRs by directly phosphorylating the receptors and inhibiting receptor coupling to GTP binding proteins. These studies could lead to a fundamental advance in our understanding of the mechanisms involved in regulation hippocampal function and could have important implications regarding novel approaches to treatment of disorders involving pathological changes in the hippocampus.

海马体在许多正常生理过程和各种病理状况（包括阿尔茨海默病和颞叶癫痫）中发挥着重要作用。 对海马功能调节所涉及的分子和细胞机制的全面了解可能会导致治疗这些疾病的新策略。直到最近，人们还认为谷氨酸（海马体中主要的兴奋性神经递质）的所有作用都是由配体门控阳离子通道的激活介导的。然而，现在很清楚，谷氨酸还可以激活代谢型谷氨酸受体 (mGluR)，该受体通过 GTP 结合蛋白与效应系统偶联。 mGluR 在调节海马细胞兴奋性和突触传递方面发挥着许多重要作用。 要全面了解正常和病理性海马功能，需要详细了解 mGluR 在调节海马生理学中的作用以及参与调节这一重要受体家族成员信号传导的分子机制。已通过分子克隆鉴定出八种 m(GluR1 - mGluR8) 亚型。在海马中，有证据表明 m(GluR2、mGluR7 和 mGluR8 均位于突触前谷氨酸能神经末梢，在那里它们可能起到抑制谷氨酸释放的作用。然而，mGluR7 和 mGluR8 的假定作用 调节特定海马突触的传递尚未明确确定。 我们最近报道，mGluR 介导的谷氨酸释放调节可以通过蛋白激酶 C (PKC) 的激活来抑制。然而，目前，PKC 抑制突触前 mGluR 信号传导的机制尚不清楚。提出了一系列研究，其中结合了解剖学、药理学和 遗传学方法将用于严格检验 mGluR7 和 m(GluR8 在两个主要海马突触中作为突触前受体的假设。然后，我们将采用生化、电生理学和分子方法来严格检验 PKC 的激活通过直接磷酸化受体和抑制受体来抑制突触前 mGluR 功能的假设 与 GTP 结合蛋白偶联。这些研究可能使我们对海马功能调节机制的理解取得根本性进展，并且可能对治疗涉及海马病理变化的疾病的新方法产生重要影响。