Signaling via G-protein-coupled receptors (GPCRs) is central for the function of biological systems. Many clinically used drugs target GPCRs directly or target molecules involved in GPCR signaling. As an alternative to targeting receptors directly, one could modulate signaling cascades downstream of receptor activation. In recent years, there has been substantial interest in a family of proteins called regulators of G protein signaling (RGS) proteins. They modulate GPCR signaling by accelerating GTP hydrolysis on active Galpha subunits, thereby reducing the amplitude and duration of signaling. Modulating RGS activity would be a useful strategy to control GPCR signaling. An RGS inhibitor would be expected to enhance GPCR signaling and could do so in a tissue- or pathway-specific manner. Apart from the central GAP (GTPase accelerating protein) activity, many RGS proteins also have other functions like regulating protein-protein interactions, subcellular localization of signaling molecules, and protein translation. It is clear that these proteins serve important functions in a number of physiological and pathophysiological processes, and they are emerging as potential drug targets. This chapter gives an overview of what is currently known about biological functions of RGS proteins based on in vivo and in vitro data. We also summarize the current status in targeting RGS proteins in drug discovery.
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