Regulators of G protein signaling (RGS) proteins have emerged in the past two decades as novel drug targets in many areas of research. Their importance in regulating signaling via G protein-coupled receptors has become evident as numerous studies have been published on the structure and function of RGS proteins. A number of genetic models have also been developed, demonstrating the potential clinical importance of RGS proteins in various disease states, including central nervous system disorders, cardiovascular disease, diabetes, and several types of cancer. Apart from their classical mechanism of action as GTPase-activating proteins (GAPs), RGS proteins can also serve other noncanonical functions. This opens up a new approach to targeting RGS proteins in drug discovery as the view on the function of these proteins is constantly evolving. This chapter summarizes the latest development in RGS protein drug discovery with special emphasis on noncanonical functions and regulatory mechanisms of RGS protein expression. As more reports are being published on this group of proteins, it is becoming clear that modulation of GAP activity might not be the only way to therapeutically target RGS proteins.
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