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β-Blockers alprenolol and carvedilol stimulate β-arrestin-mediated EGFR transactivation

Kim, Il-Man, Tilley, Douglas G., Chen, Juhsien, Salazar, Natasha C., Whalen, Erin J., Violin, Jonathan D., Rockman, Howard A.
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.38 pp. 14555-14560
G-protein coupled receptors, agonists, antagonists, beta-adrenergic antagonists, ligands, mitogen-activated protein kinase, mutants, phosphorylation, signal transduction, small interfering RNA, transcriptional activation
Recent evidence suggests that binding of agonist to its cognate receptor initiates not only classical G protein-mediated signaling, but also β-arrestin-dependent signaling. One such β-arrestin-mediated pathway uses the β₁-adrenergic receptor (β₁AR) to transactivate the EGFR. To determine whether β-adrenergic ligands that do not activate G protein signaling (i.e., β-blockers) can stabilize the β₁AR in a signaling conformation, we screened 20 β-blockers for their ability to stimulate β-arrestin-mediated EGFR transactivation. Here we show that only alprenolol (Alp) and carvedilol (Car) induce β₁AR-mediated transactivation of the EGFR and downstream ERK activation. By using mutants of the β₁AR lacking G protein-coupled receptor kinase phosphorylation sites and siRNA directed against β-arrestin, we show that Alp- and Car-stimulated EGFR transactivation requires β₁AR phosphorylation at consensus G protein-coupled receptor kinase sites and β-arrestin recruitment to the ligand-occupied receptor. Moreover, pharmacological inhibition of Src and EGFR blocked Alp- and Car-stimulated EGFR transactivation. Our findings demonstrate that Alp and Car are ligands that not only act as classical receptor antagonists, but can also stimulate signaling pathways in a G protein-independent, β-arrestin-dependent fashion.