GRK2 and Beta-Arrestins in Cardiovascular Disease: Established and Emerging Possibilities for Therapeutic Targeting

Heptahelical G protein-coupled receptors, such as the -adrenergic and the angiotensin II type 1 receptors, are the most diverse and therapeutically important family of receptors in the human genome, playing major roles in the physiology of various organs/tissues including the heart and blood vessels. Ligand binding activates heterotrimeric G proteins that transmit intracellular signals by regulating effector enzymes or ion channels. G protein signaling is terminated, in large part, by phosphorylation of the agonist-bound receptor by the family of G-protein coupled receptor kinases (GRKs), with GRK2 being its most prominent member, followed by barrestin binding, which uncouples the phosphorylated receptor and G protein and subsequently targets the receptor for internalization. As the receptor-barrestin complex enters the cell, barrestins serve as ligand-regulated scaffolds that recruit a host of intracellular proteins and signal transducers, thus promoting their own wave of signal transduction independently of G-proteins. A large number of preclinical studies in small and large animals over the past several years have pinpointed specific pathophysiologic roles played by these two families of receptor-regulating proteins in various cardiovascular diseases, directly implicating them in disease pathology and suggesting them as potential therapeutic targets. The present review gives an account of what is currently known about the benefits of cardiac and adrenal GRK2 inhibition for cardiovascular disease treatment, and also discusses the exciting new therapeutic possibilities emerging from uncovering the physiological roles of arrestin-mediated signaling in vivo in the cardiovascular system.