Arrestins in the Cardiovascular System: An Update

Three major functional roles for the two ubiquitous G protein-coupled receptor (GPCR) adapter proteins, βarrestin1 and -2 (also known as Arrestin2 and -3, respectively), have been described: (a) functional desensitization, i.e., G-protein uncoupling from the receptor, (b) GPCR internalization via clathrin-coated pits, and (c) formation of signalosomes. Either while bound to the GPCR or after dissociating from it, and either while trafficking inside the cell or from the plasma membrane, both βarrestins are known to mediate a large part of the G protein-independent signaling elicited by GPCRs. The latter constitute the single most commonly targeted receptor class by FDA-approved cardiovascular drugs, with about one-third of all currently used in the clinic medications affecting GPCR function. After initially activating heterotrimeric G proteins, most of these receptors can switch their intracellular signaling to other, G protein-independent, pathways, which are usually βarrestin-dependent. Since cardiovascular GPCRs are at the interface between hormonal actions and regulation of the circulation, cardiovascular βarrestins, by regulating these receptors in the heart, vasculature, platelets, adrenals, and other organs/tissues, play important roles in the functional regulation of the normal healthy circulatory system as well as in its dysregulation in disease. One important aspect in the study of these promiscuous signal transducers is the fact that the two βarrestin isoforms display vast, in some cases contrasting, differences in their biological functions in several organ systems, including in the systemic circulation. In this chapter, we provide an update on the physiology and pharmacology of the two βarrestins throughout the cardiovascular system and on how current knowledge can be utilized therapeutically. We also highlight the functional diversity of the two βarrestins in the circulatory system, particularly in the heart, and its impact on the translational potential of cardiovascular βarrestin therapeutic targeting.