Lei Chon Lok, Clark Alexander P, Clerx Michael, Wei Siyu, Bloothooft Meye, de Boer Teun P, Christini David J, Krogh-Madsen Trine, Mirams Gary R
Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau, 999078, China.
Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macau, 999078, China.
Adv Sci (Weinh). 2025 Aug;12(30):e00691. doi: 10.1002/advs.202500691. Epub 2025 Jun 6.
Cellular electrophysiology underpins fields from basic science in neurology, cardiology, and oncology to safety critical applications for drug safety testing, risk assessment of rare mutations, and models based on cellular electrophysiology data even guide clinical interventions. Patch-clamp voltage clamp is the gold standard for measuring ionic current dynamics that explain cellular electrophysiology, but recordings can be influenced by artifacts introduced by the measurement process. A computational approach is developed, validated through electrical model cell experiments, to explain and predict intricate artifacts in voltage-clamp experiments. Applied to various cardiac fast sodium current measurements, the model resolved artifacts in the experiments by coupling observed current with simulated membrane voltage, explaining some typically observed shifts and delays in recorded currents. It is shown that averaging data for current-voltage relationships can introduce biases comparable to effect sizes reported for disease-causing mutations. The computational pipeline provides improved assessment and interpretation of voltage-clamp experiments, correcting, and enhancing understanding of ion channel behavior.
细胞电生理学支撑着从神经学、心脏病学和肿瘤学的基础科学到药物安全性测试、罕见突变风险评估等安全关键应用的各个领域，基于细胞电生理学数据的模型甚至可指导临床干预。膜片钳电压钳是测量解释细胞电生理学的离子电流动力学的金标准，但记录可能会受到测量过程引入的伪迹的影响。开发了一种通过电模型细胞实验验证的计算方法，以解释和预测电压钳实验中的复杂伪迹。应用于各种心脏快速钠电流测量时，该模型通过将观察到的电流与模拟膜电压耦合来解析实验中的伪迹，解释了记录电流中一些典型观察到的偏移和延迟。结果表明，对电流-电压关系的数据进行平均会引入与致病突变报告的效应大小相当的偏差。该计算流程可改进电压钳实验的评估和解释，校正并增强对离子通道行为的理解。
