Epac2 Mediates Cardiac beta 1-Adrenergic-Dependent Sarcoplasmic Reticulum Ca2+ Leak and Arrhythmia

Article

关键词: PROTEIN-KINASE-II;    AFFECT CALCIUM SPARKS;    RYANODINE RECEPTOR;    HEART-FAILURE;    VENTRICULAR MYOCYTES;    UP-REGULATION;    C-EPSILON;    CAMP;    ACTIVATION;    PHOSPHORYLATION;   

DOI  :  10.1161/CIRCULATIONAHA.12.148619

来源: SCIE

【 摘 要 】

Background-beta-Adrenergic receptor (beta-AR) activation can provoke cardiac arrhythmias mediated by cAMP-dependent alterations of Ca2+ 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) Ca2+ release that involves Ca2+/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 Ca2+ leak and arrhythmias and whether it requires Epac1 versus Epac2, beta(1)-AR versus beta(2)-AR, and CaMKII delta-dependent phosphorylation of RyR2-S2814. We used knockout (KO) mice for Epac1, Epac2, or both. All KOs 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 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 Ca2+ leak and was prevented by blockade of beta(1)-AR but not beta(2)-AR. CaMKII inhibition (KN93) and genetic ablation of either CaMKII delta or CaMKII phosphorylation on RyR2-S2814 prevented 8-CPT-induced SR Ca2+ leak. Conclusions-beta(1)-AR activates Epac2 to induce SR Ca2+ leak via CaMKIId-dependent phosphorylation of RyR2-S2814. This pathway contributes to beta-AR-induced arrhythmias and reduced cardiac function. (Circulation. 2013;127:913-922.)

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