Not all arrestins are created equal: Therapeutic implications of the functional diversity of the β-arrestins in the heart

Abstract

The two ubiquitous, outside the retina, G protein-coupled receptor (GPCR) adapter proteins, β-arrestin-1 and -2 (also known as arrestin-2 and -3, respectively), have three major functions in cells: GPCR desensitization, i.e., receptor decoupling from G-proteins; GPCR internalization via clathrin-coated pits; and signal transduction independently of or in parallel to G-proteins. Both β-arrestins are expressed in the heart and regulate a large number of cardiac GPCRs. The latter constitute the single most commonly targeted receptor class by Food and Drug Administration-approved cardiovascular drugs, with about one-third of all currently used in the clinic medications affecting GPCR function. Since β-arrestin-1 and -2 play important roles in signaling and function of several GPCRs, in particular of adrenergic receptors and angiotensin II type 1 receptors, in cardiac myocytes, they have been a major focus of cardiac biology research in recent years. Perhaps the most significant realization coming out of their studies is that these two GPCR adapter proteins, initially thought of as functionally interchangeable, actually exert diametrically opposite effects in the mammalian myocardium. Specifically, the most abundant of the two β-arrestin-1 exerts overall detrimental effects on the heart, such as negative inotropy and promotion of adverse remodeling post-myocardial infarction (MI). In contrast, β-arrestin-2 is overall beneficial for the myocardium, as it has anti-apoptotic and anti-inflammatory effects that result in attenuation of post-MI adverse remodeling, while promoting cardiac contractile function. Thus, design of novel cardiac GPCR ligands that preferentially activate β-arrestin-2 over β-arrestin-1 has the potential of generating novel cardiovascular therapeutics for heart failure and other heart diseases.

Keywords: Adverse remodeling; β-arrestin; Biased signaling; Cardiac myocyte; Cardiac fibroblast; contractility; Functional divergence; G protein-coupled receptor; Heart failure; Hormone; Myocardial infarction; Signal transducer

Core tip: Presumed functionally similar for a long time, we now know that the two β-arrestins display significant functional diversity in several organs and tissues, including in the cardiovascular system. Their functional distinction also in the mammalian heart has been clearly documented over the past few years. β-arrestin-1, which is far more abundant than β-arrestin-2 in almost every tissue including the myocardium, opposes the cyclic adenosine monophosphate (cAMP)-dependent pro-contractile signaling of the β₁ adrenergic receptor (β₁AR), and promotes cardiac apoptosis, inflammation, and other adverse remodeling-associated processes post-myocardial infarction. Conversely, β-arrestin-2 promotes catecholamine-dependent cardiac contractility directly, via SERCA2a potentiation, and indirectly, by leaving β₁AR’s cAMP-dependent pro-contractile signaling unaffected.