β-Arrestin-mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection

Takahisa Noma, Anthony Lemaire, Sathyamangla V. Naga Prasad, Liza Barki-Harrington, Douglas G. Tilley, Juhsien Chen, Philippe Le Corvoisier, Jonathan D. Violin, Huijun Wei, Robert J. Lefkowitz, Howard A. Rockman

Research output: Contribution to journalArticle

Abstract

Deleterious effects on the heart from chronic stimulation of β-adrenergic receptors (βARs), 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 β-arrestins mediate β1AR signaling to the EGFR. This β-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 β-arrestin-mediated cytoprotective pathways, would represent a novel class of agents that could be developed for multiple members of the 7 transmembrane receptor family.

Original languageEnglish (US)
Pages (from-to)2445-2448
Number of pages4
JournalJournal of Clinical Investigation
Volume117
Issue number9
DOIs
StatePublished - Sep 4 2007
Externally publishedYes

ASJC Scopus subject areas

  • Medicine(all)

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    Noma, T., Lemaire, A., Naga Prasad, S. V., Barki-Harrington, L., Tilley, D. G., Chen, J., Le Corvoisier, P., Violin, J. D., Wei, H., Lefkowitz, R. J., & Rockman, H. A. (2007). β-Arrestin-mediated β1-adrenergic receptor transactivation of the EGFR confers cardioprotection. Journal of Clinical Investigation, 117(9), 2445-2448. https://doi.org/10.1172/JCI31901