PHYSIOLOGICAL ROLES OF METABOTROPIC GLUTAMATE RECEPTORS

代谢型谷氨酸受体的生理作用

• 批准号: 2892415
• 负责人: Stephen R Ikeda
• 金额: $ 23.06万
• 依托单位: GUTHRIE FOUNDATION FOR EDUCATION AND RES
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2892415
• 关键词: G protein; biological signal transduction; calcium channel blockers; cerebral cortex; electrophysiology; glutamate receptor; hippocampus; laboratory rat; microinjections; neural transmission; neurons; neurotransmitter metabolism; potassium channel; protein structure function; receptor coupling; receptor expression; sectioning; single cell analysis; voltage /patch clamp

Metabotropic glutamate receptors (mGluRs) compromise a unique subfamily of G-protein couple receptors for which glutamate is the endogenous ligand. A number of physiological roles have been ascribed to mGluRs including ion channel modulation, regulation of neurotransmitter release, and participation in synaptic plasticity such as long-term potentiation and depression. Moreover, recent evidence suggests that mGluRs could play a role in pathological processes related to epilepsy, ischemia, excitotoxic neurodegenerative disorders, Alzheimer's Disease, and hypertension. Thus there is a substantial interest in defining the roles subserved by specific mGluR subtypes and developing subtype specific pharmacological agents. At present, the sequences for twelve mGluR subtypes (mGluR1-8 plus splice variants) have been elucidated. However, despite this wealth of primary sequence information, little is known about which specific mGluR subtypes modulate ion channels and synaptic transmission in neurons or the mechanisms involved in these actions. To address this void in our knowledge, we will examine the function, pharmacology, and signal transduction pathways of: 1) heterologously expressed mGluRs in sympathetic neurons (SPECIFIC AIMS 1 and 2), and 2) natively expressed mGluRs in CNS neurons (SPECIFIC AIMS 3 and 4). Accordingly, the SPECIFIC AIMS are: 1) Pharmacological characterization and signal transduction pathways of defined mGluR subtypes that inhibit N-type Ca2+ and M-type K+ channels. Molecularly defined mGluR subtypes will be heterologously expressed in mature rat sympathetic neurons to determine which subtypes modulate N-type Ca2+ and M-type K+ channels. 2) Molecular elements of mGluR structure/function. The structural domains of mGluRs which determine pharmacological profile and G-protein coupling specificity will be examined by expressing chimeric mGluR constructs in sympathetic neurons. 3) Identification and signal transduction pathways of mGluRs involved in Ca2+ and K+ channel modulation in isolated CNS neurons. The pharmacological (agonist and antagonist) profile and signal transduction characteristics of mGluR-mediated Ca2+ and K+ channel inhibition will be determined in acutely isolated hippocampal and cortical neurons. 4) Identification of mGluRs involved in modulation of synaptic transmission in CNS neurons. Glutamatergic synaptic transmission in brain slices will be examined to determine which mGluRs mediate modulate neurotransmitter release.

代谢性谷氨酸受体（mglurs）损害了独特的亚家族 G蛋白夫妇受体的谷氨酸是内源性的 配体。许多生理角色已归因于mglurs 包括离子通道调制，神经递质调节 释放并参与突触可塑性，例如长期 增强和抑郁。此外，最近的证据表明 mglurs可以在与癫痫有关的病理过程中发挥作用， 缺血，兴奋性神经退行性疾病，阿尔茨海默氏病， 和高血压。因此，定义 特定的MGlur亚型和发展亚型的角色 特定的药理剂。目前，十二个序列 MGlur亚型（MGLUR1-8加剪接变体）已阐明。 但是，尽管有大量的主要序列信息，但很少 知道哪种特定MGLUR子类型调节离子通道和 神经元中的突触传播或这些机制 动作。为了解决这一空白，我们将研究 功能，药理学和信号转导途径：1） 在交感神经元中异源表达的mglurs（特定目的 1和2）和2）在中枢神经系统中固有表达的mglurs（特定 目标3和4）。因此，具体目的是：1）药理学 定义MGlur的表征和信号转导途径 抑制N型Ca2+和M型K+通道的亚型。分子 定义的mglur亚型将在成熟的大鼠中异源表达 交感神经元确定哪种亚型调节N型Ca2+ 和M型K+通道。 2）mglur的分子元素 结构/功能。确定的mglurs的结构域 药理学特征和G蛋白偶联特异性将是 通过以同情的方式表达嵌合mglur构造来检查 神经元。 3）MGLURS的识别和信号转导途径 在分离的CNS神经元中参与Ca2+和K+通道调制。这 药理学（激动剂和拮抗剂）和信号 MGLUR介导的Ca2+和K+通道的转导特性 抑制作用将在急性分离的海马和 皮质神经元。 4）识别参与调制的mglurs 中枢神经系统神经元中的突触传播。谷氨酸能突触 将检查大脑切片中的传输以确定哪些mglurs 中介调节神经递质释放。