Department of Pharmacology and Pharmacotherapy, University of Szeged, Dóm tér 12. H-6720 Szeged, Hungary.
Curr Med Chem. 2011;18(24):3622-39. doi: 10.2174/092986711796642463.
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 Ca(2+) concentration (Ca(2+)). Direct regulation via interaction between Ca(2+ ) and the channel protein or indirect modulation via Ca(2+ ) 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 Ca(2+ ) 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 (I(to1) and I(K1)) with documented Ca(2+)-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 Ca(2+ )-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.
正常的心脏功能和心肌动作电位（AP）复极化在很大程度上取决于肌膜 K(+)通道的同步活动，这在心室和心房心肌中都有表达，对静息电位、起搏活动以及 AP 的形状和持续时间的调节有很大贡献。临床观察和心肌细胞及多细胞制剂的实验研究为一些主要外向 K+电流和相应的离子通道对细胞内 Ca(2+)浓度变化的敏感性提供了确凿的证据(Ca(2+))。通过 Ca(2+)与通道蛋白的直接相互作用或通过这些电流的 Ca(2+)信号通路的间接调节，对心脏的机械和电性能及其对改变负荷的生理适应有很强的影响。如果在各种病理条件下 Ca(2+ )处理受到干扰，也可能导致严重的心脏功能障碍。在这篇综述中，我们试图总结目前关于两种普遍存在的复极化 K(+)电流（I(to1)和 I(K1)）的研究现状，这些电流具有已证明的 Ca(2+)-敏感性和在细胞抗心律失常防御中的关键意义，突出线索数据缺失的领域，并讨论心脏小电导 Ca(2+)-激活 K(+)（SK）通道明显未解决的“谜团”。我们收集了关于这些已知新型电流的可用信息，尽管通常仍然没有足够的选择性抑制剂和激活剂，这证明需要更具选择性的抑制剂和激活剂。最后，我们强调了一些相关的治疗学观点，以供未来的实验研究，特别是药物开发中考虑。
