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

For many years, beta-adrenergic receptor antagonists (beta-blockers or beta AR antagonists) have provided significant morbidity and mortality benefits in patients who have sustained acute myocardial infarction. More recently, beta-adrenergic receptor antagonists have been found to provide survival benefits in patients suffering from heart failure, although the efficacy of different beta-blockers varies widely in this condition. One drug, carvedilol, a nonsubtypeselective beta 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 beta AR antagonists, carvedilol displays a unique profile of in vitro signaling characteristics. We observed that in 132 adrenergic receptor (1;2AR)-expressing HEK-293 cells, carvedilol has inverse efficacy for stimulating G.-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 beta-arrestin to the beta 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 beta 2AR(T68F,Y132G,Y219A) (beta 2AR(TYY)) and abolished by beta-arrestin2 siRNA. Taken together, these data indicate that carvedilol is able to stabilize a receptor conformation which, although uncoupled from G., is nonetheless able to stimulate beta-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 beta 2AR ligands.