A unique mechanism of -blocker action: Carvedilol stimulates -arrestin signaling

For many years, -adrenergic receptor antagonists ( -blockers or AR antagonists) have provided significant morbidity and mortality benefits in patients who have sustained acute myocardial infarction. More recently, -adrenergic receptor antagonists have been found to provide survival benefits in patients suffering from heart failure, although the efficacy of different -blockers varies widely in this condition. One drug, carvedilol, a nonsubtypeselective AR antagonist, has proven particularly effective in the treatment of heart failure, although the mechanism(s) responsible for this are controversial. Here, we report that among 16 clinically relevant AR antagonists, carvedilol displays a unique profile of in vitro signaling characteristics. We observed that in 2 adrenergic receptor ( 2AR)-expressing HEK-293 cells, carvedilol has inverse efficacy for stimulating Gs-dependent adenylyl cyclase but, nonetheless, stimulates (i) phosphorylation of the receptor’s cytoplasmic tail on previously documented G protein-coupled receptor kinase sites; (ii) recruitment of -arrestin to the 2AR; (iii) receptor internalization; and (iv) activation of extracellular regulated kinase 1/2 (ERK 1/2), which is maintained in the G protein-uncoupled mutant 2ART68F,Y132G,Y219A ( 2ARTYY) and abolished by arrestin2 siRNA. Taken together, these data indicate that carvedilol is able to stabilize a receptor conformation which, although uncoupled from Gs, is nonetheless able to stimulate -arrestinmediated signaling. We hypothesize that such signaling may contribute to the special efficacy of carvedilol in the treatment of heart failure and may serve as a prototype for a new generation of therapeutic 2AR ligands.