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

Magali Berthouze-Duquesnes 1 Alexandre Lucas 1 Aude Saulière 1 Yuan Yan Sin 2 Anne-Coline Laurent 1 Céline Galés 1 George Baillie 2 Frank Lezoualc'H 1, *
* Auteur correspondant
1 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires
2 Institute of Cardiovascular and Medical Sciences [Glasgow]
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.
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Cell Signal, 2013, 25 (4), pp.970-80. 〈10.1016/j.cellsig.2012.12.007〉
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http://www.hal.inserm.fr/inserm-01010399
Contributeur : Marie Francoise Simon <>
Soumis le : jeudi 19 juin 2014 - 16:24:04
Dernière modification le : jeudi 4 octobre 2018 - 09:50:10

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Magali Berthouze-Duquesnes, Alexandre Lucas, Aude Saulière, Yuan Yan Sin, Anne-Coline Laurent, et al.. Specific interactions between Epac1, β-arrestin2 and PDE4D5 regulate β-adrenergic receptor subtype differential effects on cardiac hypertrophic signaling.. Cell Signal, 2013, 25 (4), pp.970-80. 〈10.1016/j.cellsig.2012.12.007〉. 〈inserm-01010399〉

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