| First Author | Pereira L | Year | 2013 |
| Journal | Circulation | Volume | 127 |
| Issue | 8 | Pages | 913-22 |
| PubMed ID | 23363625 | Mgi Jnum | J:210426 |
| Mgi Id | MGI:5571030 | Doi | 10.1161/CIRCULATIONAHA.12.148619 |
| Citation | Pereira L, et al. (2013) Epac2 mediates cardiac beta1-adrenergic-dependent sarcoplasmic reticulum Ca2+ leak and arrhythmia. Circulation 127(8):913-22 |
| abstractText | BACKGROUND: beta-Adrenergic receptor (beta-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 beta-AR activation causes Epac-mediated SR Ca(2+) leak and arrhythmias and whether it requires Epac1 versus Epac2, beta(1)-AR versus beta(2)-AR, and CaMKIIdelta-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. beta-AR-induced arrhythmias were also less inducible in Epac2-KO versus wild-type mice. beta-AR activation with protein kinase A inhibition mimicked 8-CPT effects on SR Ca(2+) leak and was prevented by blockade of beta(1)-AR but not beta(2)-AR. CaMKII inhibition (KN93) and genetic ablation of either CaMKIIdelta or CaMKII phosphorylation on RyR2-S2814 prevented 8-CPT-induced SR Ca(2+) leak. CONCLUSIONS: beta(1)-AR activates Epac2 to induce SR Ca(2+) leak via CaMKIIdelta-dependent phosphorylation of RyR2-S2814. This pathway contributes to beta-AR-induced arrhythmias and reduced cardiac function. |
