Epac2 Mediates Cardiac β1-Adrenergic–Dependent Sarcoplasmic Reticulum Ca 2+ Leak and Arrhythmia

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Background— β-Adrenergic receptor (β-AR) activation can provoke cardiac arrhythmias mediated by cAMP-dependent alterations of Ca 2+ signaling. However, cAMP can activate both protein kinase A and an exchange protein directly activated by cAMP (Epac), but their functional interaction is unclear. In heart, selective Epac activation can induce potentially arrhythmogenic sarcoplasmic reticulum (SR) Ca 2+ release that involves Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) effects on the ryanodine receptor (RyR). Methods and Results— We tested whether physiological β-AR activation causes Epac-mediated SR Ca 2+ leak and arrhythmias and whether it requires Epac1 versus Epac2, β 1 -AR versus β 2 -AR, and CaMKIIδ-dependent phosphorylation of RyR2-S2814. We used knockout (KO) mice for Epac1, Epac2, or both. All KOs exhibited unaltered basal cardiac function, Ca 2+ handling, and hypertrophy in response to pressure overload. However, SR Ca 2+ leak induced by the specific Epac activator 8-CPT in wild-type mice was abolished in Epac2-KO and double-KO mice but was unaltered in Epac1-KO mice. β-AR–induced arrhythmias were also less inducible in Epac2-KO versus wild-type mice. β-AR activation with protein kinase A inhibition mimicked 8-CPT effects on SR Ca 2+ leak and was prevented by blockade of β 1 -AR but not β 2 -AR. CaMKII inhibition (KN93) and genetic ablation of either CaMKIIδ or CaMKII phosphorylation on RyR2-S2814 prevented 8-CPT–induced SR Ca 2+ leak. Conclusions— β 1 -AR activates Epac2 to induce SR Ca 2+ leak via CaMKIIδ-dependent phosphorylation of RyR2-S2814. This pathway contributes to β-AR–induced arrhythmias and reduced cardiac function.