Techniques:: Promiscuous Gα proteins in basic research and drug discovery

Assay technologies that measure the activation of heterotrimeric (alpha beta gamma) G proteins by G-protein-coupled receptors (GPCRs) are well established within the pharmaceutical industry, either for pharmacological characterization or for the identification of natural or surrogate receptor ligands. Despite recent evidence indicating that GPCR-linked signalling events might not be mediated exclusively by G proteins, G-protein activation remains a common benchmark for assessing GPCR family members. Thus, assay systems that translate ligand-mediated modulation of GPCRs into G-protein-dependent intracellular responses still represent key components of both basic research and the drug discovery process. In this article, the current knowledge and recent progress of integrating G alpha subunits into assay systems for GPCR drug discovery will be reviewed. Emphasis is given to novel promiscuous and chimeric G alpha proteins. Because of their ability to interact with a wide range of GPCRs, such novel G proteins are likely to be incorporated rapidly into drug discovery programmes.