Beta-Arrestin-Mediated Signaling in the Heart

• Published in: Circulation Journal Vol. 72; no. 11; pp. 1725 - 1729
• Main Authors: Patel, Priyesh A., Tilley, Douglas G., Rockman, Howard A.
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Circulation Society 2008
• Subjects: Adrenergic beta-1 Receptor Agonists; Animals; Arrestins - metabolism; Beta-1-adrenergic receptor; Beta-arrestin; beta-Arrestins; Chronic Disease; Disease Models, Animal; ErbB Receptors - agonists; ErbB Receptors - metabolism; Extracellular regulated kinase (ERK); Extracellular Signal-Regulated MAP Kinases - metabolism; G protein-coupled receptor; Heart Failure - drug therapy; Heart Failure - metabolism; Humans; MAP Kinase Signaling System; Myocardium - metabolism; Receptor, Angiotensin, Type 1 - agonists; Receptor, Angiotensin, Type 1 - metabolism; Receptors, Adrenergic, beta-1 - metabolism
• ISSN: 1346-9843; 1347-4820
• DOI: 10.1253/circj.CJ-08-0734

Beta-arrestin is a multifunctional adapter protein well known for its role in G-protein-coupled receptor (GPCR) desensitization. Exciting new evidence indicates that β-arrestin is also a signaling molecule capable of initiating its own G-protein-independent signaling at GPCRs. One of the best-studied β-arrestin signaling pathways is the one involving β-arrestin-dependent activation of a mitogen-activated protein kinase cascade, the extracellular regulated kinase (ERK). ERK signaling, which is classically activated by agonist stimulation of the epidermal growth factor receptor (EGFR), can be activated by a number of GPCRs in a β-arrestin-dependent manner. Recent work in animal models of heart failure suggests that β-arrestin-dependent activation of EGFR/ERK signaling by the β-1-adrenergic receptor, and possibly the angiotensin II Type 1A receptor, are cardioprotective. Hence, a new model of signaling at cardiac GPCRs has emerged and implicates classical G-protein-mediated signaling with promoting harmful remodeling in heart failure, while concurrently linking β-arrestin-dependent, G-protein-independent signaling with cardioprotective effects. Based on this paradigm, a new class of drugs could be identified, termed "biased ligands", which simultaneously block harmful G-protein signaling, while also promoting cardioprotective β-arrestin-dependent signaling, leading to a potential breakthrough in the treatment of chronic cardiac disease. (Circ J 2008; 72: 1725 - 1729)