G protein-coupled receptors (GPCRs) are major targets for drug discovery. They offer innumerable therapeutic benefits through the promotion or inhibition of GPCR-mediated biochemical, physiological and disease processes. The detailed understanding of how GPCRs detect extracellular signals and transduce them to intracellular G proteins and second messenger pathways has led to the development and exploitation of chimeric and promiscuous G protein a subunits. These adaptors, such as qi5, Gα16 and 16z44, allow signals from diverse GPCRs to be directed to the generation of an easily detectable product. This has enabled almost any GPCR to be incorporated into screening platforms such as FLIPR, aequorin assays, yeast autocrine selection and microarrayed assays. In this review we will revisit the structure of GPCRs and heterotrimeric G proteins with particular reference to those regions that determine the specificity of their interaction. In light of this information we will follow the development of chimeric Gα subunits and the discovery of naturally promiscuous adaptors. Their utility is exemplified by their incorporation into high-throughput drug screening assays and GPCR deorphanization programs.
Keywords: gpcr, g protein, chimera, drug screening, deorphanization, flipr
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