Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection.
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.
Noma
Takahisa
T
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Lemaire
Anthony
A
Naga Prasad
Sathyamangla V
SV
Barki-Harrington
Liza
L
Tilley
Douglas G
DG
Chen
Juhsien
J
Le Corvoisier
Philippe
P
Violin
Jonathan D
JD
Wei
Huijun
H
Lefkowitz
Robert J
RJ
Rockman
Howard A
HA
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