KChIP2 regulates the cardiac Ca2+ transient and myocyte contractility by targeting ryanodine receptor activity.
KChIP2 regulates the cardiac Ca2+ transient and myocyte contractility by targeting ryanodine receptor activity.
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DOI：
10.1371/journal.pone.0175221
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Deschênes I
中科院分区：
文献类型：
--
作者：
Nassal DM;Wan X;Liu H;Laurita KR;Deschênes I
病理性电重构和心肌收缩能力减弱是心力衰竭的特征。与这些重塑事件相一致的是K+通道相互作用蛋白KChIP2的丢失。虽然KChIP2增强了Kv4家族钾通道的表达和稳定性，导致了更明显的瞬时外向钾电流Ito，f，但豚鼠心肌的独特之处在于Kv4的表达缺失，而KChIP2的表达得到了保留，这可能是KChIP2丢失的另一种后果。因此，KChIP2在分离的豚鼠心肌细胞上被急性沉默，导致钙瞬变幅度显著降低，瞬变时程延长。肌节缩短的下降加强了这一变化。值得注意的是，这些结果是出乎意料的，因为考虑到之前的观察显示，KChIP2丢失后ICa、L增强和动作电位持续时间延长，这表明基本的钙调节蛋白被破坏。对SERCA2a、磷蛋白、RyR和钠钙交换蛋白的评估表明，蛋白表达没有变化。然而，对钙火花活性的评估显示，KChIP2丢失后，放电频率降低，钙衰变时间延长，这表明RyR的活性状态发生了变化。这些变化与Ryanodine受体激活剂早老素的离域化有关，远离肌节带而分布更弥漫，表明RyR开放概率是KChIP2的靶点，由早老素的解离介导。通常，延长的动作电位时程和增强的钙离子内流会增强心肌的收缩能力，但这里我们看到KChIP2从根本上扰乱了钙释放事件，并损害了心肌细胞的收缩。这种针对早老素定位和RyR活性的新角色揭示了KChIP2丢失的意义，KChIP2丢失反映了在心脏病环境中观察到的不利重构。
Pathologic electrical remodeling and attenuated cardiac contractility are featured characteristics of heart failure. Coinciding with these remodeling events is a loss of the K+ channel interacting protein, KChIP2. While, KChIP2 enhances the expression and stability of the Kv4 family of potassium channels, leading to a more pronounced transient outward K+ current, Ito,f, the guinea pig myocardium is unique in that Kv4 expression is absent, while KChIP2 expression is preserved, suggesting alternative consequences to KChIP2 loss. Therefore, KChIP2 was acutely silenced in isolated guinea pig myocytes, which led to significant reductions in the Ca2+ transient amplitude and prolongation of the transient duration. This change was reinforced by a decline in sarcomeric shortening. Notably, these results were unexpected when considering previous observations showing enhanced ICa,L and prolonged action potential duration following KChIP2 loss, suggesting a disruption of fundamental Ca2+ handling proteins. Evaluation of SERCA2a, phospholamban, RyR, and sodium calcium exchanger identified no change in protein expression. However, assessment of Ca2+ spark activity showed reduced spark frequency and prolonged Ca2+ decay following KChIP2 loss, suggesting an altered state of RyR activity. These changes were associated with a delocalization of the ryanodine receptor activator, presenilin, away from sarcomeric banding to more diffuse distribution, suggesting that RyR open probability are a target of KChIP2 loss mediated by a dissociation of presenilin. Typically, prolonged action potential duration and enhanced Ca2+ entry would augment cardiac contractility, but here we see KChIP2 fundamentally disrupts Ca2+ release events and compromises myocyte contraction. This novel role targeting presenilin localization and RyR activity reveals a significance for KChIP2 loss that reflects adverse remodeling observed in cardiac disease settings.