For many years,
beta-adrenergic receptor antagonists (beta-blockers or betaAR 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 nonsubtype-selective betaAR 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 betaAR antagonists,
carvedilol displays a unique profile of in vitro signaling characteristics. We observed that in beta2
adrenergic receptor (beta2AR)-expressing HEK-293 cells,
carvedilol has inverse efficacy for stimulating G(s)-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 beta2AR; (iii) receptor internalization; and (iv) activation of extracellular regulated
kinase 1/2 (ERK 1/2), which is maintained in the
G protein-uncoupled mutant beta2AR(T68F,Y132G,Y219A) (beta2AR(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(s), is nonetheless able to stimulate
beta-arrestin-mediated 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 beta2AR
ligands.