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.