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

► β1AR but not β2AR activates Epac1-Ras hypertrophic signaling. ► Ras activation requires Epac1 recruitment to β1AR via β-arrestin2. ► Epac1 competes with PDE4D5 to interact with β-arrestin2 under β2AR activation. ► Dissociation of PDE4D5 from β-arrestin2 renders β2AR signaling prohypertrophic. ► This study enlightens mechanisms responsible for βARs opposing biological effects.