Specific interactions between Epac1, β-arrestin2 and PDE4D5 regulate β-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling

Berthouze-Duquesnes, M., Lucas, A., Saulière, A., Sin, Y.Y., Laurent, A.C., Galés, C., Baillie, G. and Lezoualc'h, F. (2013) Specific interactions between Epac1, β-arrestin2 and PDE4D5 regulate β-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling. Cellular Signalling, 25(4), pp. 970-980. (doi: 10.1016/j.cellsig.2012.12.007) (PMID:23266473)

Full text not currently available from Enlighten.

Abstract

β1 and β2 adrenergic receptors (βARs) are highly homologous but fulfill distinct physiological and pathophysiological roles. Here we show that both βAR subtypes activate the cAMP-binding protein Epac1, but they differentially affect its signaling. The distinct effects of βARs on Epac1 downstream effectors, the small G proteins Rap1 and H-Ras, involve different modes of interaction of Epac1 with the scaffolding protein β-arrestin2 and the cAMP-specific phosphodiesterase (PDE) variant PDE4D5. We found that β-arrestin2 acts as a scaffold for Epac1 and is necessary for Epac1 coupling to H-Ras. Accordingly, knockdown of β-arrestin2 prevented Epac1-induced histone deacetylase 4 (HDAC4) nuclear export and cardiac myocyte hypertrophy upon β1AR activation. Moreover, Epac1 competed with PDE4D5 for interaction with β-arrestin2 following β2AR activation. Dissociation of the PDE4D5–β-arrestin2 complex allowed the recruitment of Epac1 to β2AR and induced a switch from β2AR non-hypertrophic signaling to a β1AR-like pro-hypertrophic signaling cascade. These findings have implications for understanding the molecular basis of cardiac myocyte remodeling and other cellular processes in which βAR subtypes exert opposing effects.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Baillie, Professor George and Sin, Dr Angie
Authors: Berthouze-Duquesnes, M., Lucas, A., Saulière, A., Sin, Y.Y., Laurent, A.C., Galés, C., Baillie, G., and Lezoualc'h, F.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Cellular Signalling
Publisher:Elsevier
ISSN:0898-6568
ISSN (Online):1873-3913
Published Online:22 December 2012

University Staff: Request a correction | Enlighten Editors: Update this record