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

beta 1 and beta 2 adrenergic receptors (beta ARs) are highly homologous but fulfill distinct physiological and pathophysiological roles. Here we show that both beta AR subtypes activate the cAMP-binding protein Epac1, but they differentially affect its signaling. The distinct effects of beta ARs on Epac1 downstream effectors, the small G proteins Rap1 and H-Ras, involve different modes of interaction of Epac1 with the scaffolding protein beta-arrestin2 and the cAMP-specific phosphodiesterase (PDE) variant PDE4D5. We found that beta-arrestin2 acts as a scaffold for Epac1 and is necessary for Epac1 coupling to H-Ras. Accordingly, knockdown of beta-arrestin2 prevented Epac1-induced histone deacetylase 4 (HDAC4) nuclear export and cardiac myocyte hypertrophy upon beta 1AR activation. Moreover, Epac1 competed with PDE4D5 for interaction with beta-arrestin2 following beta 2AR activation. Dissociation of the PDE4D5-beta-arrestin2 complex allowed the recruitment of Epac1 to beta 2AR and induced a switch from beta 2AR non-hypertrophic signaling to a beta 1AR-like pro-hypertrophic signaling cascade. These findings have implications for understanding the molecular basis of cardiac myocyte remodeling and other cellular processes in which beta AR subtypes exert opposing effects. (C) 2012 Elsevier Inc. All rights reserved.