Epac in cardiac calcium signaling.

Epac, exchange protein directly activated by cAMP, is emerging as a new regulator of cardiac physiopathology. Although its effects are much less known than the classical cAMP effector, PKA, several studies have investigated the cardiac role of Epac, providing evidences that Epac modulates intracellular Ca(2+). In one of the first analyses, it was shown that Epac can increase the frequency of spontaneous Ca(2+) oscillations in cultured rat cardiomyocytes. Later on, in adult cardiomyocytes, it was shown that Epac can induce sarcoplasmic reticulum (SR) Ca(2+) release in a PKA independent manner. The pathway identified involved phospholipase C (PLC) and Ca(2+)/calmodulin kinase II (CaMKII). The latter phosphorylates the ryanodine receptor (RyR), increasing the Ca(2+) spark probability. The RyR, Ca(2+) release channel located in the SR membrane, is a key element in the excitation-contraction coupling. Thus Epac participates in the excitation-contraction coupling. Moreover, by inducing RyR phosphorylation, Epac is arrhythmogenic. A detailed analysis of Ca(2+) mobilization in different microdomains showed that Epac preferently elevated Ca(2+) in the nucleoplasm ([Ca(2+)]n). This effect, besides PLC and CaMKII, required inositol 1,4,5 trisphosphate receptor (IP3R) activation. IP3R is other Ca(2+) release channel located mainly in the perinuclear area in the adult ventricular myocytes, where it has been shown to participate in the excitation-transcription coupling (the process by which Ca(2+) activates transcription). If Epac activation is maintained for some time, the histone deacetylase (HDAC) is translocated out of the nucleus de-repressing the transcription factor myocyte enhancer factor (MEF2). These evidences also pointed to Epac role in activating the excitation-transcription coupling. In fact, it has been shown that Epac induces cardiomyocyte hypertrophy. Epac activation for several hours, even before the cell hypertrophies, induces a profound modulation of the excitation-contraction coupling: increasing the [Ca(2+)]i transient amplitude and cellular contraction. Thus Epac actions are rapid but time and microdomain dependent in the cardiac myocyte. Taken together the results collected indicate that Epac may have an important role in the cardiac response to stress.