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, Howard A. Rockman

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)14555-14560
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number38
DOIs
StatePublished - Sep 23 2008
Externally publishedYes

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Alprenolol
Arrestin
Transcriptional Activation
Adrenergic Receptors
G-Protein-Coupled Receptor Kinases
GTP-Binding Proteins
Ligands
Phosphorylation
Adrenergic Agents
Small Interfering RNA
carvedilol
Pharmacology

Keywords

  • β-adrenergic receptor
  • G protein-coupled receptor
  • Signaling

ASJC Scopus subject areas

  • General

Cite this

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.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 38, 23.09.2008, p. 14555-14560.

Research output: Contribution to journalArticle

Kim, Il Man ; Tilley, Douglas G. ; Chen, Juhsien ; Salazar, Natasha C. ; Whalen, Erin J. ; Violin, Jonathan D. ; Rockman, Howard A. / β-Blockers alprenolol and carvedilol stimulate β-arrestin- mediated EGFR transactivation. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 38. pp. 14555-14560.
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