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

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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.