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PNAS 105 (38): 14555-14560

Copyright © 2008 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MEDICAL SCIENCES

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

Il-Man Kim*, Douglas G. Tilley*, Juhsien Chen*, Natasha C. Salazar*, Erin J. Whalen*, Jonathan D. Violin*, and Howard A. Rockman*,{dagger},{ddagger},§

Departments of *Medicine, {dagger}Cell Biology, and {ddagger}Molecular Genetics, Duke University Medical Center, Durham, NC 27710

Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and accepted by the Editorial Board August 1, 2008

Received for publication May 16, 2008.

Abstract: 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.

Key Words: β-adrenergic receptor • G protein-coupled receptor • signaling


Author contributions: I.-M.K., D.G.T., J.C., N.C.S., and H.A.R. designed research; I.-M.K., D.G.T., J.C., N.C.S., E.J.W., and J.D.V. performed research; I.-M.K., D.G.T., J.C., N.C.S., E.J.W., and J.D.V. analyzed data; and I.-M.K. and H.A.R. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0804745105/DCSupplemental.

§To whom correspondence should be addressed. E-mail: h.rockman{at}duke.edu

© 2008 by The National Academy of Sciences of the USA

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