Beta-arrestin-mediated signaling in the heart.
Beta-arrestin is a multifunctional adapter protein well known for its role in G-protein-coupled receptor (GPCR) desensitization. Exciting new evidence indicates that beta-arrestin is also a signaling molecule capable of initiating its own G-protein-independent signaling at GPCRs. One of the best-studied beta-arrestin signaling pathways is the one involving beta-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 beta-arrestin-dependent manner. Recent work in animal models of heart failure suggests that beta-arrestin-dependent activation of EGFR/ERK signaling by the beta-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 beta-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 beta-arrestin-dependent signaling, leading to a potential breakthrough in the treatment of chronic cardiac disease.
School of Medicine, Duke University, Durham, NC, USA.
Priyesh A
PA
Patel
Douglas G
DG
Tilley
Howard A
HA
Rockman
D058665:Adrenergic beta-1 Receptor Agonists; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002908:Chronic Disease; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000819:agonists / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D009206:Myocardium / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D000071557:beta-Arrestins
D058665:Adrenergic beta-1 Receptor Agonists; D019390:Arrestins; D044140:Receptor, Angiotensin, Type 1; D018342:Receptors, Adrenergic, beta-1; D000071557:beta-Arrestins; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases