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

• 作者: Anastasios Lymperopoulos Celina M Pollard Jennifer Maning Katie A McCrink Shelby L Wertz Victoria L Desimine
• 来源期刊: 世界心脏病学杂志:英文版(电子版)
• 学科: 医学
• 关键词: Adverse remodeling β-arrestin Biased signaling CARDIAC MYOCYTE CARDIAC fibroblast CONTRACTILITY Functional divergence G protein-coupled receptor HEART failure Hormone Myocardial infarction Signal transducer
• 年，卷（期）: 2019,（2）
• 页码范围: 47-56
• 页数: 10页
• 分类号: R977.6

摘要

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.Bothβ-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 onethird of all currently used in the clinic medications affecting GPCR function.Sinceβ-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 antiinflammatory effects that result in attenuation of post-MI adverse remodeling,while promoting cardiac contractile function.Thus,design of novel cardiac GPCR ligands that preferentially activateβ-arrestin-2 overβ-arrestin-1 has the potential of generating novel cardiovascular therapeutics for heart failure and other heart diseases.