Calmodulin kinase II and protein kinase C mediate the effect of increased intracellular calcium to augment late sodium current in rabbit ventricular myocytes
Calmodulin kinase II and protein kinase C mediate the effect of increased intracellular calcium to augment late sodium current in rabbit ventricular myocytes
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钙调蛋白激酶 II 和蛋白激酶 C 介导细胞内钙增加增加兔心室肌细胞晚钠电流的作用
DOI：
10.1152/ajpcell.00374.2011
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发表时间：
2012-04-01
影响因子：
5.5
通讯作者：
Belardinelli, Luiz
中科院分区：
文献类型：
--
作者：
Ma, Jihua;Luo, Antao;Belardinelli, Luiz
[10] Ma J，Luo A，Wu L，Wan W，Zhang P，Ren Z，Zhang S，Qian C，Shryock JC，Belardinelli L.钙调蛋白激酶II和蛋白激酶C介导细胞内钙增加对兔心室肌细胞晚期钠电流的影响。美国生理学杂志细胞生理学302：C1141-C1151，2012年。首次发表于2011年12月21日; doi：10.1152/ajpcell.00374.2011。心肌细胞内Ca ~（2+）浓度（[Ca ~（2+）]（i））的增加增强了心肌细胞的晚钠电流（I-Na.L）。本研究验证了Ca 2 +-钙调素依赖性蛋白激酶II（CaMKII）和蛋白激酶C（PKC）介导[Ca 2 +]（i）增加I-Na. L的作用的假设。本文用全细胞和开放细胞膜片钳技术记录了不同浓度[Ca ~（2+）]（i）透析的兔心室肌细胞的I-Na·L。用0.1 - 0.3、0.6和1.0 μ M的[Ca 2 +]（i）透析细胞，以浓度依赖性方式使I-Na.L从0.221 +/- 0.038增加到0.554 +/- 0.045 pA/pF（n = 10，P < 0.01），并与平均Na+通道开放概率增加和平均开放时间延长相关（n = 7，P < 0.01）。在0.6 μ M [Ca ~（2+）]（i）存在下，KN-93（10 μ M）和双吲哚马来酰亚胺（BIM，2 μ M）分别使I-Na.L降低45.2%和54.8%。KN-93和autocamtide-2相关抑制肽II（2 μ M）的作用没有差异。KN-93和BIM的组合完全逆转了I-Na.L的增加以及Ca 2+诱导的Na+通道平均开放概率和平均开放时间的变化（0.6 μ M [Ca 2 +]（i））。佛波醇肉豆蔻酰乙酸酯增加了0.1 μ M [Ca 2 +]透析的肌细胞中的I-Na.L（i）; Go-6976消除了该作用。总之，CaMKII和PKC均参与[Ca 2 +]（i）介导的心室肌细胞中I-Na.L增加。抑制CaMKII和/或PKC通路可能是减少由钙超载引起的心肌功能障碍和心律失常的治疗靶点。
Ma J, Luo A, Wu L, Wan W, Zhang P, Ren Z, Zhang S, Qian C, Shryock JC, Belardinelli L. Calmodulin kinase II and protein kinase C mediate the effect of increased intracellular calcium to augment late sodium current in rabbit ventricular myocytes. Am J Physiol Cell Physiol 302: C1141-C1151, 2012. First published December 21, 2011; doi:10.1152/ajpcell.00374.2011.-An increase in intracellular Ca2+ concentration ([Ca2+](i)) augments late sodium current (I-Na.L) in cardiomyocytes. This study tests the hypothesis that both Ca2+-calmodulin-dependent protein kinase II (CaMKII) and protein kinase C (PKC) mediate the effect of increased [Ca2+](i) to increase I-Na.L. Whole cell and open cell-attached patch clamp techniques were used to record I-Na.L in rabbit ventricular myocytes dialyzed with solutions containing various concentrations of [Ca2+](i). Dialysis of cells with [Ca2+](i) from 0.1 to 0.3, 0.6, and 1.0 mu M increased I-Na.L in a concentration-dependent manner from 0.221 +/- 0.038 to 0.554 +/- 0.045 pA/pF (n = 10, P < 0.01) and was associated with an increase in mean Na+ channel open probability and prolongation of channel mean open-time (n = 7, P < 0.01). In the presence of 0.6 mu M [Ca2+](i), KN-93 (10 mu M) and bisindolylmaleimide (BIM, 2 mu M) decreased I-Na.L by 45.2 and 54.8%, respectively. The effects of KN-93 and autocamtide-2-related inhibitory peptide II (2 mu M) were not different. A combination of KN-93 and BIM completely reversed the increase in I-Na.L as well as the Ca2+-induced changes in Na+ channel mean open probability and mean open-time induced by 0.6 mu M [Ca2+](i). Phorbol myristoyl acetate increased I-Na.L in myocytes dialyzed with 0.1 mu M [Ca2+](i); the effect was abolished by Go-6976. In summary, both CaMKII and PKC are involved in [Ca2+](i)-mediated augmentation of I-Na.L in ventricular myocytes. Inhibition of CaMKII and/or PKC pathways may be a therapeutic target to reduce myocardial dysfunction and cardiac arrhythmias caused by calcium overload.