Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A G Protein-Biased Ligand at the {mu}-Opioid Receptor Is Potently Analgesic with Reduced Gastrointestinal and Respiratory Dysfunction Compared with Morphine.
S. M. DeWire, D. S. Yamashita, D. H. Rominger, G. Liu, C. L. Cowan, T. M. Graczyk, X.-T. Chen, P. M. Pitis, D. Gotchev, C. Yuan, et al. (2013)
J. Pharmacol. Exp. Ther. 344, 708-717
   Abstract »    Full Text »    PDF »
Cardiotoxic and Cardioprotective Features of Chronic {beta}-Adrenergic Signaling.
X. Zhang, C. Szeto, E. Gao, M. Tang, J. Jin, Q. Fu, C. Makarewich, X. Ai, Y. Li, A. Tang, et al. (2013)
Circ. Res. 112, 498-509
   Abstract »    Full Text »    PDF »
MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound {beta}2-adrenergic receptors.
S.-o. Han, K. Xiao, J. Kim, J.-H. Wu, J. W. Wisler, N. Nakamura, N. J. Freedman, and S. K. Shenoy (2012)
J. Cell Biol. 199, 817-830
   Abstract »    Full Text »    PDF »
Induction of Cardiac Fibrosis by {beta}-Blocker in G Protein-independent and G Protein-coupled Receptor Kinase 5/{beta}-Arrestin2-dependent Signaling Pathways.
M. Nakaya, S. Chikura, K. Watari, N. Mizuno, K. Mochinaga, S. Mangmool, S. Koyanagi, S. Ohdo, Y. Sato, T. Ide, et al. (2012)
J. Biol. Chem. 287, 35669-35677
   Abstract »    Full Text »    PDF »
Biasing the Prostaglandin F2{alpha} Receptor Responses toward EGFR-Dependent Transactivation of MAPK.
E. Goupil, V. Wisehart, E. Khoury, B. Zimmerman, S. Jaffal, T. E. Hebert, and S. A. Laporte (2012)
Mol. Endocrinol. 26, 1189-1202
   Abstract »    Full Text »    PDF »
Nuclear GPCRs in cardiomyocytes: an insider's view of {beta}-adrenergic receptor signaling.
G. Vaniotis, B. G. Allen, and T. E. Hebert (2011)
Am J Physiol Heart Circ Physiol 301, H1754-H1764
   Abstract »    Full Text »    PDF »
Treatment of Chronic Heart Failure With {beta}-Adrenergic Receptor Antagonists: A Convergence of Receptor Pharmacology and Clinical Cardiology.
M. R. Bristow (2011)
Circ. Res. 109, 1176-1194
   Abstract »    Full Text »    PDF »
Airway Epithelial Epidermal Growth Factor Receptor Mediates Hogbarn Dust-Induced Cytokine Release but Not Ca2+ Response.
P. R. Dodmane, N. A. Schulte, A. J. Heires, H. Band, D. J. Romberger, and M. L. Toews (2011)
45, 882-888
   Abstract »    Full Text »    PDF »
Distinct Phosphorylation Sites on the {beta}2-Adrenergic Receptor Establish a Barcode That Encodes Differential Functions of {beta}-Arrestin.
K. N. Nobles, K. Xiao, S. Ahn, A. K. Shukla, C. M. Lam, S. Rajagopal, R. T. Strachan, T.-Y. Huang, E. A. Bressler, M. R. Hara, et al. (2011)
Science Signaling 4, ra51
   Abstract »    Full Text »    PDF »
Biased Ligands for Better Cardiovascular Drugs: Dissecting G-Protein-Coupled Receptor Pharmacology.
S. M. DeWire and J. D. Violin (2011)
Circ. Res. 109, 205-216
   Abstract »    Full Text »    PDF »
G Protein-Dependent and G Protein-Independent Signaling Pathways and Their Impact on Cardiac Function.
D. G. Tilley (2011)
Circ. Res. 109, 217-230
   Abstract »    Full Text »    PDF »
{beta}-Arrestin mediates oxytocin receptor signaling, which regulates uterine contractility and cellular migration.
C. A. Grotegut, L. Feng, L. Mao, R. P. Heine, A. P. Murtha, and H. A. Rockman (2011)
Am J Physiol Endocrinol Metab 300, E468-E477
   Abstract »    Full Text »    PDF »
Functional Selectivity in Adrenergic and Angiotensin Signaling Systems.
C. B. Patel, N. Noor, and H. A. Rockman (2010)
Mol. Pharmacol. 78, 983-992
   Abstract »    Full Text »    PDF »
{beta}-Arrestin-Biased Agonism of the Angiotensin Receptor Induced by Mechanical Stress.
K. Rakesh, B. Yoo, I.-M. Kim, N. Salazar, K.-S. Kim, and H. A. Rockman (2010)
Science Signaling 3, ra46
   Abstract »    Full Text »    PDF »
Beyond Desensitization: Physiological Relevance of Arrestin-Dependent Signaling.
L. M. Luttrell, D. Gesty-Palmer, and D. R. Sibley (2010)
Pharmacol. Rev. 62, 305-330
   Abstract »    Full Text »    PDF »
{beta}-Arrestin Mediates {beta}1-Adrenergic Receptor-Epidermal Growth Factor Receptor Interaction and Downstream Signaling.
D. G. Tilley, I.-M. Kim, P. A. Patel, J. D. Violin, and H. A. Rockman (2009)
J. Biol. Chem. 284, 20375-20386
   Abstract »    Full Text »    PDF »
Arrestin Times for Developing Antipsychotics and {beta}-Blockers.
M. D. Houslay (2009)
Science Signaling 2, pe22
   Abstract »    Full Text »    PDF »
{beta}2-Adrenoceptor signaling is required for the development of an asthma phenotype in a murine model.
L. P. Nguyen, R. Lin, S. Parra, O. Omoluabi, N. A. Hanania, M. J. Tuvim, B. J. Knoll, B. F. Dickey, and R. A. Bond (2009)
PNAS 106, 2435-2440
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882