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

G蛋白偶联受体（GPCR）信号通路的三个主要元件是受体（GPCR）、传感器（异源三聚体G蛋白）和下游效应分子（酶/通道）。确定每个组成部分的作用是必要的，以了解细胞如何能够和将要对各种外部刺激作出反应，并制定策略，专门干预这些过程。长期以来，G蛋白的作用仅限于其作为细胞外刺激（通过受体）和下游效应物之间的介质的定义角色。近年来，研究表明G蛋白，特别是gβ和γ亚基在细胞中发挥着许多其他作用，其中两个是调节含有受体和效应器的信号复合物的组装和直接控制基因表达。目前的研究项目将试图通过使用涉及线虫C. elegans的简单遗传系统来了解5种人类Gbeta和12种人类gamma亚型的不同作用。我们将敲除两个内源性的G β或γ亚基，并用单个的哺乳动物同源物取代它们，以观察(1)它们的正常功能是否得到恢复或(2)新功能是否出现。这些研究将使我们能够更好地理解细胞信号传导的“粒度”，因为Gbetagamma亚基随着时间的推移而进化。

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.