Reuter Hannes, Pott Christian, Goldhaber Joshua I, Henderson Scott A, Philipson Kenneth D, Schwinger Robert H G
Laboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine III, University of Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany.
Cardiovasc Res. 2005 Aug 1;67(2):198-207. doi: 10.1016/j.cardiores.2005.04.031.
Cardiac sarcolemmal Na(+)--Ca(2+) exchange is a central component of Ca2+ signaling essential for Ca2+ extrusion and contributing to a variable degree to the development of the systolic Ca2+ transient. Reports on differential gene expression of Na(+)--Ca2+ exchange in cardiac disease and the regulation of its thermodynamic equilibrium depending on intracellular gradients of ion concentrations between subcellular compartments have recently put a new complexion on Na(+)--Ca2+ exchange and its implications for excitation-contraction (E-C) coupling. Heart failure models and genetic approaches to regulate expression of the Na(+)--Ca2+ exchanger have improved our knowledge of exchanger function. Modest overexpression of the Na(+)--Ca2+ exchanger in heterozygous transgenic mice had minimal effects on E-C coupling and cardiac function. However, higher levels of Na(+)--Ca2+ exchange expression in homozygotes led to pathological hypertrophy and failure with an increased interaction between the L-type Ca2+ current and Na(+)--Ca2+ exchange and reduced E-C coupling gain. These results suggested that the Na(+)--Ca2+ exchanger is capable of modulating sarcoplasmic Ca2+ handling and at high expression levels may interact with the gating kinetics of the L-type Ca2+ current by means of regulating subsarcolemmal Ca2+ levels. Despite being a central component in the regulation of cardiac E-C coupling, a newly generated mouse model with cardiac-specific conditional knock-out of the Na(+)--Ca2+ exchanger is viable with unchanged Ca2+ dynamics in adult ventricular myocytes. Cardiac myocytes adapt well to knock-out of the exchanger, apparently by reducing transsarcolemmal fluxes of Ca2+ and increasing E-C coupling gain possibly mediated by changes in submembrane Ca2+ levels. For E-C coupling in the murine model, which relies primarily on sarcoplasmic Ca2+ regulation, this led to the suggestion that the role of Na(+)--Ca2+ exchange should be thought of as a Ca2+ buffering function and not as a major Ca2+ transporter in competition with the sarcoplasmic reticulum.
心肌肌膜钠钙交换是钙信号传导的核心组成部分，对钙的排出至关重要，并在不同程度上影响收缩期钙瞬变的产生。最近有关心脏病中钠钙交换的差异基因表达以及其热力学平衡取决于亚细胞区室之间离子浓度的细胞内梯度调节的报道，为钠钙交换及其对兴奋 - 收缩（E-C）偶联的影响带来了新的认识。心力衰竭模型以及调节钠钙交换体表达的遗传学方法增进了我们对交换体功能的了解。在杂合转基因小鼠中适度过表达钠钙交换体对E-C偶联和心脏功能影响极小。然而，纯合子中更高水平的钠钙交换体表达导致病理性肥大和功能衰竭，L型钙电流与钠钙交换体之间的相互作用增加，E-C偶联增益降低。这些结果表明，钠钙交换体能够调节肌浆钙的处理，在高表达水平时可能通过调节肌膜下钙水平与L型钙电流的门控动力学相互作用。尽管钠钙交换是心脏E-C偶联调节的核心组成部分，但新生成的心脏特异性条件性敲除钠钙交换体的小鼠模型是可行的，成年心室肌细胞中的钙动力学未发生改变。心肌细胞显然通过减少跨肌膜钙通量并增加可能由膜下钙水平变化介导的E-C偶联增益，很好地适应了交换体的敲除。对于主要依赖肌浆钙调节的小鼠模型中的E-C偶联而言，这表明应将钠钙交换的作用视为一种钙缓冲功能，而不是与肌浆网竞争的主要钙转运体。
