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.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1172/JCI31901

Publication Info

Noma, Takahisa, Anthony Lemaire, Sathyamangla V Naga Prasad, Liza Barki-Harrington, Douglas G Tilley, Juhsien Chen, Philippe Le Corvoisier, Jonathan D Violin, et al. (2007). Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Invest, 117(9). pp. 2445–2458. 10.1172/JCI31901 Retrieved from https://hdl.handle.net/10161/5925.

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Scholars@Duke

Rockman

Howard Allan Rockman

Edward S. Orgain Distinguished Professor of Cardiology, in the School of Medicine

Rockman Lab: Molecular Mechanisms of Hypertrophy and Heart Failure

Overall Research Direction: The major focus of this laboratory is to understand the molecular mechanisms of hypertrophy and heart failure. My laboratory uses a strategy that combines state of the art molecular techniques to generate transgenic and gene targeted mouse models, combined with sophisticated physiologic measures of in vivo cardiac function. In this manner, candidate molecules are either selectively overexpressed in the mouse heart or genes ablated followed by an in-depth analysis of the physiological phenotype. To model human cardiac disease, we have created several models of cardiac overload in the mouse using both microsurgical techniques and genetic models of cardiac dysfunction.

Areas of Research
1) Signaling: G protein-coupled receptor signaling in hypertrophy and heart failure focusing on the concept of biased signaling of 7 transmembrane receptors.

2) Molecular physiology: In depth physiological analysis of cardiac function in genetically altered mice to understand the role of G protein-coupled receptor signaling pathways on the development of heart failure in vivo.


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