Understanding the specificity of Gbetagamma signalling using C. elegans as a model.

使用线虫作为模型了解 Gbetagamma 信号传导的特异性。

• 批准号: 238344-2012
• 负责人: Hébert, Terence
• 金额: $ 3.5万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=570400
• 关键词: Understanding; specificity; Gbetagamma; signalling; using

The three major elements of G protein-coupled receptor (GPCR) signalling pathways are receptors (GPCRs), transducers (heterotrimeric G protein) and downstream effector molecules (enzymes/channels). Identifying the roles of each component is necessary to understand how the cell can and will respond to various external stimuli and to develop strategies to specifically intervene in these processes. For a long time, the role of G proteins was limited to its defined roles as the mediator between an extracellular stimulus (via the receptor) and downstream effectors. Recently, it has been shown that G proteins, in particular Gbeta and Ggamma subunits play many other roles in the cell, two of which are to regulate assembly of signalling complexes containing receptors and effectors and to directly control gene expression. The current research project will attempt to understand distinct roles for 5 human Gbeta and 12 human Ggamma isoforms by using a simple genetic system involving the nematode worm, C. elegans. We will knock down the two endogenous G beta or Ggamma subunits and replace them with invididual mammalian homologs to see if (1) their normal functions are rescued or (2) new functions emerge. These studies will allow us to better understand the "granularity" of cell signalling as Gbetagamma subunits evolved over time.

G蛋白偶联受体(GPCRs)信号通路的三个主要元件是受体(GPCRs)、转导分子(异源三聚体G蛋白)和下游效应分子(酶/通道)。确定每个成分的作用对于了解细胞能够和将如何对各种外部刺激做出反应以及制定具体干预这些过程的策略是必要的。在很长一段时间里，G蛋白的作用仅限于其作为细胞外刺激(通过受体)和下游效应器之间的中介作用。最近的研究表明，G蛋白，特别是Gβ和Gγ亚基在细胞中还有许多其他作用，其中两个是调节含有受体和效应器的信号复合体的组装，并直接控制基因的表达。目前的研究项目将试图通过使用一个涉及线虫线虫的简单遗传系统来了解5个人类Gbeta和12个人类GGamma亚型的不同角色。我们将敲除两个内源性Gβ或GGamma亚基，并用哺乳动物自身的同源物取代它们，看看(1)它们的正常功能是否得到挽救，或(2)新功能是否出现。这些研究将使我们更好地理解细胞信号的“粒度”，因为Gbetagamma亚单位随着时间的推移而进化。