In-Silico Modeling of the Functional Role of Reduced Sialylation in Sodium and Potassium Channel Gating of Mouse Ventricular Myocytes
In-Silico Modeling of the Functional Role of Reduced Sialylation in Sodium and Potassium Channel Gating of Mouse Ventricular Myocytes
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DOI：
10.1109/jbhi.2017.2664579
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发表时间：
2018-03-01
影响因子：
7.7
通讯作者：
Bennett, Eric S.
中科院分区：
文献类型：
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作者：
Du, Dongping;Yang, Hui;Bennett, Eric S.
心脏离子通道是高度糖基化的膜蛋白，其中高达30%的蛋白质质量含有聚糖。心脏病常伴随先天性糖基化障碍（CDG）。然而，CDG患者的心功能障碍尚未完全了解。目前迫切需要研究异常糖基化如何影响心脏电信号。我们以前的工作报道，通过缺失唾液酸转移酶基因ST 3Gal 4实现的先天性唾液酸化减少，导致电压门控Na+和K+通道（分别为Na-v和K-v）门控改变。然而，在不进行计算机实验的情况下，将减少的唾液酸化对离子通道门控的影响与动作电位（AP）联系起来是困难的。此外，分解K+电流的总和是困难的，因为K-v通道的复杂结构和组分（例如，K-v 4.2和K-v 1.5）。在这项研究中，我们开发了计算机模拟模型，使用体外实验数据来描述减少的唾液酸化在Na-v和K-v门控以及AP中的功能作用。模拟结果表明，减少唾液酸化改变K-v门控如下：1）K-v亚型的稳态激活电压移动到更去极化的电位。2)异常K+电流（I-Kslow和I-to）导致AP持续时间延长，而改变的Na+电流（I-Na）导致AP不应期缩短。这项研究有助于更好地了解唾液酸化减少在心功能不全中的功能作用，显示出为治疗CDG相关心脏疾病提供新的药物靶点的强大潜力。
Cardiac ion channels are highly glycosylated membrane proteins with up to 30% of the protein's mass containing glycans. Heart diseases often accompany individuals with congenital disorders of glycosylation (CDG). However, cardiac dysfunction among CDG patients is not yet fully understood. There is an urgent need to study how aberrant glycosylation impacts cardiac electrical signaling. Our previous works reported that congenitally reduced sialylation achieved through deletion of the sialyltransferase gene, ST3Gal4, leads to altered gating of voltage-gated Na+ and K+ channels (Na-v and K-v, respectively). However, linking the impact of reduced sialylation on ion channel gating to the action potential (AP) is difficult without performing computer experiments. Also, decomposing the sum of K+ currents is difficult because of complex structures and components of K-v channels (e.g., K-v 4.2, and K-v 1.5). In this study, we developed in-silico models to describe the functional role of reduced sialylation in both Na-v and K-v gating and the AP using in vitro experimental data. Modeling results showed that reduced sialylation changes K-v gating as follows: 1) The steady-state activation voltages of K-v isoforms are shifted to a more depolarized potential. 2) Aberrant K+ currents (I-Kslow and I-to) contribute to a prolonged AP duration, and altered Na+ current (I-Na) contributes to a shortened AP refractory period. This study contributes to a better understanding of the functional role of reduced sialylation in cardiac dysfunction that shows strong potential to provide new pharmaceutical targets for the treatment of CDG-related heart diseases.