Title:GRK2 and Beta-Arrestins in Cardiovascular Disease: Established and Emerging Possibilities for Therapeutic Targeting
VOLUME: 5 ISSUE: 3
Author(s):Alicia N. Harvey, Kristy Nguyen and Anastasios Lymperopoulos
Affiliation:Department of Pharmaceutical Sciences, Nova Southeastern University College of Pharmacy, 3200 S. University Dr., HPD (Terry) Bldg/Room 1338, Ft. Lauderdale, FL, 33328, USA.
Keywords:Adrenal gland, angiotensin II type 1 receptor, β-adrenergic receptor, βarrestin signaling, cardiovascular disease,
catecholamine, GRK2, heptahelical receptor, vascular smooth muscle
Abstract:Heptahelical G protein-coupled receptors, such as the β-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 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 and adrenal GRK2 inhibition for cardiovascular disease treatment, and also discusses the exciting
new therapeutic possibilities emerging from uncovering the physiological roles of βarrestin-mediated signaling in
vivo in the cardiovascular system.
