BETA GAMMA HETERODIMER IN NEURONAL FUNCTIONG

神经元功能中的 Beta GAMMA 异二聚体

• 批准号: 6204881
• 负责人: MELVIN SIMON
• 金额: $ 16.93万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6204881
• 关键词: G protein; biological signal transduction; calcium channel; cell cell interaction; gene expression; gene targeting; genetic mapping; genetic recombination; genetically modified animals; laboratory mouse; neural information processing; neurons; neurophysiology; nucleic acid sequence; polymerase chain reaction; potassium channel; protein protein interaction; protein structure function; receptor coupling; serotonin receptor; site directed mutagenesis

G-protein signal transduction pathways are one of the major targets for a vast array of therapeutic drugs and for a variety of compounds that address problems in neurological function. In order to understand how to intervene in an effective way in these ubiquitous and complex pathways we must sort out the function of individual circuits and the mechanisms that cells use to integrate information and to elicit specific responses. We have been characterizing the nature of the protein-protein interactions that mediate information flow in intracellular signaling by generating mutants with specific properties e.g. dominant negative mutants or gene deletions, and correlating their activity in cell culture or in vivo with activity in reconstituted systems. Much of our work has focused on the activity of the various G alpha protein subunits and their effectors. However in the past few years it has become clear that the beta-gamma dimer can interact with a large number of potential effectors including sodium, potassium and calcium channels. In the next grant period we will focus on understanding the function of the beta-gamma dimer particularly as it relates to neuronal activity. We have discovered an interesting gene that encodes a novel beta isoform (beta 5) which is expressed exclusively in neural tissue. We will isolate and characterize the beta 5 gene and compare its structure to that of other beta genes and we will prepare "knockout" mice lacking beta 5 function and study their physiology. We will use site specific and random mutagenesis to define changes in beta-gamma structure that lead to differential interaction with effectors in order to determine the mechanisms that control the wide range of beta gamma activity. We will reintroduce mutants of beta-gamma into specific cells, tissues and animals in order to further define the mechanisms that regulate and integrate G-protein mediated signal transduction.

G蛋白信号转导途径是主要目标之一 用于大量的治疗药物和多种化合物 该解决神经功能的问题。为了 了解如何以有效的方式干预这些无处不在 和复杂的途径，我们必须分解个人的功能 电路和细胞用于整合信息的机制 并引起特定的回应。我们一直在描述 介导信息的蛋白质蛋白质相互作用的性质 通过产生特定的突变体，在细胞内信号传导中流动 属性，例如主要的阴性突变体或基因缺失，以及 将它们在细胞培养或体内的活性与活性相关联 在重构系统中。我们的大部分工作都集中在 各种Gα蛋白亚基及其的活性 效应子。但是在过去的几年中，很明显 Beta-Gamma二聚体可以与大量潜力相互作用 效应子，包括钠，钾和钙通道。在 下一个赠款期我们将专注于理解 β-γ二聚体特别是与神经元活性有关。 我们发现了一个有趣的基因，该基因编码一个新颖的beta 同工型（β5），仅在神经组织中表达。 我们将隔离和表征β5基因并比较其 其他β基因的结构，我们将准备“淘汰” 缺乏Beta 5功能并研究其生理的小鼠。我们将使用 位点特异性和随机诱变，以定义β-gamma的变化 导致与效应子相互作用不同的结构 为了确定控制广泛范围的机制 beta伽马活性。我们将将β-伽玛的突变体重新引入 特定的细胞，组织和动物，以进一步定义 调节和整合G蛋白介导的信号的机制 转导。