Abstract 1335: The β-blocker Alprenolol Stimulates β-arrestin Mediated Epidermal Growth Factor Receptor Transactivation
The binding of agonist to its cognate receptor initiates not only classical G protein-mediated signaling, but also G protein-coupled receptor kinase (GRK) and β-arrestin dependent signals. We recently identified a new signaling pathway in which β-arrestin mediates β1-adrenergic receptor (β1AR) transactivation of the epidermal growth factor receptor (EGFR). Activation of this β1AR-EGFR transactivation pathway provides cardioprotection in vivo under conditions of catecholamine toxicity. Recent observations suggest that binding of different β-adrenergic ligands stabilizes distinct receptor conformations, leading to specific signaling outcomes. To identify whether β-adrenergic ligands that do not activate G protein signaling can induce β-arrestin mediated EGFR transactivation, we screened 20 β-blockers using confocal microscopy in HEK 293 cells overexpressing β1AR and EGFR-GFP. We found that alprenolol consistently induced β-arrestin mediated β1AR transactivation of EGFR. Using mutants of the β1AR and siRNA directed against β-arrestin we show that alprenolol stimulated-EGFR transactivation requires both β1AR phosphorylation on the c-terminal tail and β-arrestin (see figure⇓). Moreover, pharmacological inhibition of Src and EGFR blocked alprenolol-stimulated EGFR transactivation. Our findings suggest that alprenolol may represent a novel class of drugs that provide cardioprotection via β-arrestin mediated β1AR-EGFR transactivation as well as classical antagonistic action of G protein signaling.