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)

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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:Sin, Dr Yuan Yan and Baillie, Professor George
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 > Institute of Cardiovascular and Medical Sciences
Journal Name:Cellular Signalling
Publisher:Elsevier
ISSN:0898-6568
ISSN (Online):1873-3913
Published Online:22 December 2012

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