G protein-mediated signal transduction is essential for the regulation of cardiovascular function, including heart rate, growth, contraction, and vascular tone. Regulators of G protein Signaling (RGS proteins) fine-tune G protein-coupled receptor-induced signaling by regulating its magnitude and duration through direct interaction with the α subunits of heterotrimeric G proteins. Changes in the RGS protein expression and/or function in the heart often lead to pathophysiological changes and are associated with cardiac disease in animals and humans, including hypertrophy, fibrosis development, heart failure, and arrhythmias. This article focuses on Regulator of G protein Signaling 2 (RGS2), which is widely expressed in many tissues and is highly regulated in its expression and function. Most information to date has been obtained in biochemical, cellular, and animal studies, but data from humans is emerging. We review recent advances on the functional role of cardiovascular RGS2 and the mechanisms that determine its signaling selectivity, expression, and functionality. We highlight key unanswered questions and discuss the potential of RGS2 as a therapeutic target.
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