GRK2 and β-arrestins in cardiovascular disease: Something old, something new

Heptahelical G protein-coupled 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) followed by βarrestin binding, which uncouples the phosphorylated receptor and G protein and subsequently targets the receptor for internalization. As the receptor-βarrestin complex enters the cell, βarrestins 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 GRK2 inhibition for cardiovascular disease treatment, and also discusses the exciting new therapeutic possibilities emerging from uncovering the physiological roles of adrenal GRK2 and of βarrestin-mediated signaling in vivo in the cardiovascular system.