Modulation of late sodium current by Ca2+, calmodulin, and CaMKII in normal and failing dog cardiomyocytes:: similarities and differences
Modulation of late sodium current by Ca2+, calmodulin, and CaMKII in normal and failing dog cardiomyocytes:: similarities and differences
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DOI：
10.1152/ajpheart.00484.2007
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发表时间：
2008-04-01
影响因子：
4.8
通讯作者：
Undrovinas, Albertas
中科院分区：
文献类型：
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作者：
Maltsev, Victor A.;Reznikov, Vitaliy;Undrovinas, Albertas
在人类和犬衰竭心肌中，晚期Na+电流（I-NaL）增加和减慢与动作电位时程变异性、早期后除极和异常Ca 2+处理有关。我们的目的是研究正常和衰竭心室肌细胞胞浆Ca 2+浓度（[Ca 2 +]（i））对INaL的调节。10只犬经多次冠状动脉微栓塞术制备慢性心力衰竭模型，6只正常犬作为对照。通过心室肌细胞的全细胞膜片钳测量INaL精细结构，并分别通过Na+通道门控的爆发和迟散模式产生的快和慢指数的总和来近似。当[Ca ~（2+）]（i）从“无Ca ~（2+）”增加到1 μ M时，I-NaL大大增强：其最大密度增加，两个指数的衰减减慢，稳态失活（SSI）曲线向更正的电位移动。测试CaMKII和CaM的抑制揭示了衰竭与正常肌细胞中I-NaL调节的相似性和差异。相似之处包括以下：1）CaMKII减慢I-NaL衰减并降低快速指数的幅度，以及2）Ca 2+移位SSI π。差异包括：1）CaMKII对I-NaL的减慢作用更大，2）CaM使SSI发生位移，3）Ca ~（2+）增加慢指数的幅度。我们的结论是，Ca 2 +/CaM/CaMK Ⅱ信号增加I-NaL和Na+流入正常和失败的心肌细胞通过减缓失活动力学和移位SSI。这种Na+内流提供了一种新的Ca 2+正反馈机制（通过Na+/Ca 2+交换器），在更高的跳动速率下增强收缩，但在心力衰竭中Ca 2+处理不良的条件下恶化心肌细胞收缩和电性能。
Augmented and slowed late Na+ current (I-NaL) is implicated in action potential duration variability, early afterdepolarizations, and abnormal Ca2+ handling in human and canine failing myocardium. Our objective was to study INaL modulation by cytosolic Ca2+ concentration ([Ca2+](i)) in normal and failing ventricular myocytes. Chronic heart failure was produced in 10 dogs by multiple sequential coronary artery microembolizations; 6 normal dogs served as a control. INaL fine structure was measured by whole cell patch clamp in ventricular myocytes and approximated by a sum of fast and slow exponentials produced by burst and late scattered modes of Na+ channel gating, respectively. I-NaL greatly enhanced as [Ca2+](i) increased from "Ca2+ free" to 1 mu M: its maximum density increased, decay of both exponentials slowed, and the steady-state inactivation (SSI) curve shifted toward more positive potentials. Testing the inhibition of CaMKII and CaM revealed similarities and differences of I-NaL modulation in failing vs. normal myocytes. Similarities include the following: 1) CaMKII slows I-NaL decay and decreases the amplitude of fast exponentials, and 2) Ca2+ shifts SSI rightward. Differences include the following: 1) slowing of I-NaL by CaMKII is greater, 2) CaM shifts SSI leftward, and 3) Ca2+ increases the amplitude of slow exponentials. We conclude that Ca2+/CaM/CaMKII signaling increases I-NaL and Na+ influx in both normal and failing myocytes by slowing inactivation kinetics and shifting SSI. This Na+ influx provides a novel Ca2+ positive feedback mechanism (via Na+/Ca2+ exchanger), enhancing contractions at higher beating rates but worsening cardiomyocyte contractile and electrical performance in conditions of poor Ca2+ handling in heart failure.