Epac2 Mediates Cardiac β1-Adrenergic Dependent SR Ca2+ Leak and Arrhythmia
Background-β-adrenergic receptor (β-AR) activation can provoke cardiac arrhythmias mediated by cAMP-dependent alterations of Ca2+ signaling. However cAMP can activate both PKA 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) Ca2+ release that involves CaMKII effects on the ryanodine receptor (RyR).
Methods and Results-We tested whether physiological β-AR activation causes Epac-mediated SR Ca2+ leak and arrhythmias, whether it requires Epac1 vs. Epac2, β1-AR vs. β2-AR and CaMKIIδ-dependent phosphorylation of RyR2-S2814. We used knockout mice for Epac1, Epac2 or both (DKO). All knockouts exhibited unaltered basal cardiac function, Ca2+ handling and hypertrophy in response to pressure overload. However, SR Ca2+ leak induced by the specific Epac activator 8-CPT in wild-type was abolished in Epac2-KO and DKO, but unaltered in Epac1-KO. β-AR-induced arrhythmias were also less inducible in Epac2-KO vs. wild-type. β-AR activation with PKA inhibition, mimicked 8-CPT effects on SR Ca2+ leak, and was prevented by blockade of β1-AR but not β2-AR. CaMKII inhibition (KN93) and genetic ablation of either CaMKIIδ or CaMKII phosphorylation on RyR2-S2814 prevented 8-CPT-induced SR Ca2+ leak.
Conclusions-β1-AR activates Epac2 to induce SR Ca2+ leak via CaMKIIδ-dependent phosphorylation of RyR2-S2814. This pathway contributes to β-AR-induced arrhythmias and reduced cardiac function.
- Received October 12, 2012.
- Revision received January 9, 2013.
- Accepted January 10, 2013.
- Copyright © 2013, Circulation