Department of Biomedical Engineering and the Institute for Computational Medicine, The Johns Hopkins University School of Medicine and Whiting School of Engineering, 3400 N Charles Street, Baltimore, MD 21218, USA.
J Mol Cell Cardiol. 2019 Mar;128:145-157. doi: 10.1016/j.yjmcc.2019.02.001. Epub 2019 Feb 5.
Cardiac sodium (Na) potassium ATPase (NaK) pumps, neuronal sodium channels (I), and sodium calcium (Ca) exchangers (NCX1) may co-localize to form a Na microdomain. It remains controversial as to whether neuronal I contributes to local Na accumulation, resulting in reversal of nearby NCX1 and influx of Ca into the cell. Therefore, there has been great interest in the possible roles of a Na microdomain in cardiac Ca-induced Ca release (CICR). In addition, the important role of co-localization of NaK and NCX1 in regulating localized Na and Ca levels and CICR in ankyrin-B deficient (ankyrin-B) cardiomyocytes has been examined in many recent studies. Altered Na dynamics may contribute to the appearance of arrhythmias, but the mechanisms underlying this relationship remain unclear. In order to investigate this, we present a mechanistic canine cardiomyocyte model which reproduces independent local dyadic junctional SR (JSR) Ca release events underlying cell-wide excitation-contraction coupling, as well as a three-dimensional super-resolution model of the Ca spark that describes local Na dynamics as governed by NaK pumps, neuronal I, and NCX1. The model predicts the existence of Na sparks, which are generated by NCX1 and exhibit significantly slower dynamics as compared to Ca sparks. Moreover, whole-cell simulations indicate that neuronal I in the cardiac dyad plays a key role during the systolic phase. Rapid inward neuronal I can elevate dyadic [Na] to 35-40 mM, which drives reverse-mode NCX1 transport, and therefore promotes Ca entry into the dyad, enhancing the trigger for JSR Ca release. The specific role of decreased co-localization of NaK and NCX1 in ankyrin-B cardiomyocytes was examined. Model results demonstrate that a reduction in the local NCX1- and NaK-mediated regulation of dyadic [Ca] and [Na] results in an increase in Ca spark activity during isoproterenol stimulation, which in turn stochastically activates NCX1 in the dyad. This alteration in NCX1/NaK co-localization interrupts the balance between NCX1 and NaK currents in a way that leads to enhanced depolarizing inward current during the action potential plateau, which ultimately leads to a higher probability of L-type Ca channel reopening and arrhythmogenic early-afterdepolarizations.
心脏钠 (Na) 钾 ATP 酶 (NaK) 泵、神经元钠通道 (I) 和钠钙 (Ca) 交换器 (NCX1) 可能共同定位于形成 Na 微区。神经元 I 是否有助于局部 Na 积累，导致附近 NCX1 反转和 Ca 流入细胞，这仍然存在争议。因此，人们对 Na 微区在心脏 Ca 诱导的 Ca 释放 (CICR) 中的可能作用产生了极大的兴趣。此外，ankyrin-B 缺陷 (ankyrin-B) 心肌细胞中 NaK 和 NCX1 共定位在调节局部 Na 和 Ca 水平和 CICR 中的重要作用已在许多最近的研究中得到检验。Na 动力学的改变可能导致心律失常的出现，但这种关系的机制尚不清楚。为了研究这一点，我们提出了一种机制性犬心肌细胞模型，该模型再现了独立的局部二联体连接肌浆网 (JSR) Ca 释放事件，作为细胞宽度兴奋-收缩偶联的基础，以及 Ca 火花的三维超分辨率模型，该模型描述了由 NaK 泵、神经元 I 和 NCX1 控制的局部 Na 动力学。该模型预测了 Na 火花的存在，Na 火花是由 NCX1 产生的，其动力学明显比 Ca 火花慢。此外，全细胞模拟表明，心脏二联体中的神经元 I 在收缩期起着关键作用。快速内向神经元 I 可将二联体 [Na] 升高至 35-40mM，这可驱动反向模式 NCX1 转运，从而促进 Ca 进入二联体，增强 JSR Ca 释放的触发。检查了 ankryn-B 心肌细胞中 NaK 和 NCX1 共定位减少的特定作用。模型结果表明，局部 NCX1 和 NaK 介导的二联体 [Ca] 和 [Na] 调节的减少导致异丙肾上腺素刺激时 Ca 火花活性增加，这反过来又随机激活二联体中的 NCX1。这种 NCX1/NaK 共定位的改变以一种导致动作电位平台期间去极化内向电流增加的方式打破了 NCX1 和 NaK 电流之间的平衡，最终导致 L 型 Ca 通道再开放和心律失常性早期后除极的可能性增加。
