Role of Ca2+-Sensitive K+ Currents in Controlling Ventricular Repolarization: Possible Implications for Future Antiarrhytmic Drug Therapy

N.      Nagy; Z.      Marton; L.      Kiss; A.      Varro; P.      P. Nanasi; A.      Toth

Abstract

Normal heart function and repolarization of the cardiac action potential (AP) is to a high extent subjective to synchronized activity of sarcolemmal K+ channels, expressed in both ventricular and atrial myocardium, largely contributing to regulation of the resting potential, the pacemaker activity, and the shape and duration of the AP. Clinical observations and experimental studies in cardiomyocytes and multicellular preparations provided firm evidence for the sensitivity of some major outward K+ currents and the corresponding ion channels to shifts in intracellular Ca2+ concentration ([Ca2+]i). Direct regulation via interaction between [Ca2+]i and the channel protein or indirect modulation via Ca2+ signaling pathways of these currents have strong implications to mechanical and electrical performance of the heart, and its physiological adaptation to altered load. It may also lead to severe cardiac dysfunction, if [Ca2+]i handling is disturbed in a variety of pathological conditions. In this review we attempt to summarize the present state of the topic on two ubiquitous repolarizing K+ currents (Ito1 and IK1) with documented Ca2+-sensitivity and critical significance in cellular antiarrhythmic defense, to highlight fields where clue data are missing, and discuss the apparently unsolved “mystery” of the cardiac small conductance Ca2+-activated K+ (SK) channels. We have collected the available information on the known novel, although usually still not enough selective inhibitors and activators of these currents justifying the need for more selective ones. Finally, we emphasize a few related therapeutical perspectives to be considered for future experimental research and particularly in pharmaceutical development.

Keywords: Action potential, repolarization, APD, plateau, K+ channel, Ca2+-sensitive, calmodulin, CaMKII, arrhythmia, atrial fibrillation, antiarrhythmic therapy, Ito, IK1, IKca