Epac2 mediates cardiac β1-adrenergic-dependent sarcoplasmic reticulum Ca2+ leak and arrhythmia.

ABSTRACT:

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)

SUBMITTER: Pereira L 

PROVIDER: S-EPMC3690126 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature