Abstract: Three major functional roles for the two ubiquitous G protein–coupled receptor (GPCR) adapter proteins, βarrestin1 and -2 (also known as Arrestin-2 and -3, respectively), are known: a) functional desensitization of the receptor, b) GPCR internalization via clathrin-coated pits resulting in resensitization or receptor downregulation (lysosomal degradation), and c) G protein–independent signal transduction. Both βarrestin1 and -2 can scaffold a variety of cellular effectors (or other signal transducers) to elicit signaling in their own right. βarrestin signaling usually follows the heterotrimeric G protein activation and signal transduction induced by the receptor, which appears mandatory for full activation of the agonist-GPCR-G protein ternary complex and of the receptor itself. A large portion of cardiac function is regulated by GPCRs and thus, cardiac βarrestins play important roles in the functional regulation of not only the normal healthy but also failing heart, via their actions on cardiac GPCRs. One important aspect in the study of βarrestin signaling that oftentimes gets overlooked is that signaling mediated by the two βarrestin isoforms can result in vast, even diametrically opposite, functions in various tissues and organs of the human body, including the myocardium. This needs to be accounted for in the design and development of novel biased agonist drugs for heart failure and other heart diseases. In this chapter, we provide an update on the physiology and pharmacology of the two βarrestins specifically in the myocardium. We also highlight some of the functional differences between βarrestin1 and βarrestin2 in the heart that have already been uncovered, as well as what their impact might be for the translational potential of agents targeting these two versatile proteins for heart failure treatment.
Publication Year: 2022
Publication Date: 2022-01-01
Language: en
Type: book-chapter
Indexed In: ['crossref']
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