b-arrestin-mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection

Deleterious effects on the heart from chronic stimulation of beta-adrenergic receptors (beta ARs), members of the 7 transmembrane receptor family, have classically been shown to result from G(s)-dependent adenylyl cyclase activation. Here, we identify a new signaling mechanism using both in vitro and in vivo systems whereby beta-arrestins mediate beta(1)AR signaling to the EGFP. This beta-arrestin-dependent transactivation of the EGFR, which is independent of G protein activation, requires the G protein-coupled receptor kinases 5 and 6. In mice undergoing chronic sympathetic stimulation, this novel signaling pathway is shown to promote activation of cardio-protective pathways that counteract the effects of catecholamine toxicity. These findings suggest that drugs that act as classical antagonists for G protein signaling, but also stimulate signaling via beta-arrestin-mediated cytoprotective pathways, would represent a novel class of agents that could be developed for multiple members of the 7 transmembrane receptor family.