We read with great interest the study by Pereira et al.(2007) and the accompanying Perspectives by Bers (2007) which were recently published in the The Journal of Physiology. These reports discuss a novel role for Epac, a cAMP-activated guanine nucleotide exchange factor, in the regulation of Ca2+ release during cardiac excitation–contraction (EC) coupling. The study of Pereira et al. found that electrically evoked Ca2+ release in adult rat cardiomyocytes was reduced following Epac activation by the selective activator 8-CPT. Moreover, this decrease in Ca2+ release during EC coupling was due to a Ca2+–calmodulin kinaseII (CaMKII)-dependent reduction in sarcoplasmic reticulum (SR) Ca2+ load that results from an increased frequency of Ca2+ sparks leading to SR Ca2+ leak and store depletion. While these results implicate an exciting and novel role for Epac activation in the regulation of cardiac EC coupling, they diverge with prior published results from our laboratories showing clear Epac-mediated potentiation of Ca2+ release in adult mouse ventricular myocytes (Oestreich et al. 2007). Given the divergent conclusions of the two studies, we feel that it is important to reconcile these differences by providing a fair and comprehensive comparison of the experiments conducted in both reports. Additionally, such an examination might lead to a more comprehensive understanding of the potential physiological role of the Epac signalling pathway in cardiac myocyte function. Oestreich et al.(2007) demonstrated that acute activation of Epac by 8-CPT increased electrically evoked Ca2+ release in single mouse ventricular myocytes, while 8-CPT had no effect on Ca2+ release in myocytes isolated from mice lacking phosphatidylinositol-specific phospholipase Cε (PLCε). Moreover, adenoviralmediated PLCε expression in myocytes from PLCε knockout mice restored 8-CPT enhancement of electrically evoked Ca2+ release. Thus, Epac-dependent regulation of electrically evoked Ca2+ release in the heart is entirely dependent on the presence of PLCε. This is logical because previous work by us and others demonstrated that PLCε enzymatic activity is directly regulated by Rap, making a direct connection between