Epac Effects On Cardiac Ionic Currents

The universal second messenger 3',5'-cyclic adenosine monophosphate (cAMP) has been considered for many years the main regulator of several cellular physiopathological process uniquely via protein kinase A (PKA) activation. However, in the last years the discovery of a new sensor for cAMP named Epac (exchange protein directly activated by cAMP) has profoundly changed this cAMP-PKA dogma. We have recently shown that Epac activation activates excitation-transcription coupling and, as a result, in few hours has a positive inotropic effect, which differs from acute effects. These data suggests that Epac modulates the expression of different proteins involved in excitation-contraction coupling. We analyzed the possible modulator effect of Epac on ionic currents in rat cardiac myocytes incubated or not in the presence of the selective Epac activator, 8-pCPT. We analyzed L-type Ca2+ current (ICa) and background currents by patch-clamp in the whole cell configuration. We found that while the peak of L-type Ca2+ current was not significantly altered by Epac activation, there was a shift in the voltage-dependent activation curve towards more hyperpolarized potentials. However, the voltage-dependent inactivation curve was not significantly modified by Epac. As a result, the ICa window current was higher in the Epac-activated group, which is associated with calmodulin upregulation and could contribute to the positive-inotropic effect but also induce arrhythmia. The background current was increased by Epac activation and is currently under investigation. We conclude that Epac sustained activation induce electrophysiological changes in the cardiac myocyte.