title: Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection.
abstract: Deleterious effects on the heart from chronic stimulation of beta-adrenergic receptors (betaARs), members of the 7 transmembrane receptor family, have classically been shown to result from Gs-dependent adenylyl cyclase activation. Here, we identify a new signaling mechanism using both in vitro and in vivo systems whereby beta-arrestins mediate beta1AR signaling to the EGFR. This beta-arrestin-dependent transactivation of the EGFR, which is independent of G protein activation, requires the G protein-coupled receptor kinases 5 and 6. In mice undergoing chronic sympathetic stimulation, this novel signaling pathway is shown to promote activation of cardioprotective pathways that counteract the effects of catecholamine toxicity. These findings suggest that drugs that act as classical antagonists for G protein signaling, but also stimulate signaling via beta-arrestin-mediated cytoprotective pathways, would represent a novel class of agents that could be developed for multiple members of the 7 transmembrane receptor family.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noma
authors.forename: Anthony
authors.initials: A
authors.lastname: Lemaire
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.forename: Liza
authors.initials: L
authors.lastname: Barki-Harrington
authors.forename: Douglas G
authors.initials: DG
authors.lastname: Tilley
authors.forename: Juhsien
authors.initials: J
authors.lastname: Chen
authors.forename: Philippe
authors.initials: P
authors.lastname: Le Corvoisier
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Violin
authors.forename: Huijun
authors.initials: H
authors.lastname: Wei
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lefkowitz
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D002460:Cell Line; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics*; D000071557:beta-Arrestins