Lewalle Alexandre, Niederer Steven A, Smith Nicolas P
Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St Thomas's Hospital, London, SE1 7EH, UK.
Department of Biomedical Engineering, Division of Imaging Sciences and Biomedical Engineering, King's College London, King's Health Partners, St Thomas's Hospital, London, SE1 7EH, UK
J Physiol. 2014 Dec 15;592(24):5355-71. doi: 10.1113/jphysiol.2014.279810. Epub 2014 Oct 31.
The Na(+)/K(+) ATPase (NKA) plays a critical role in maintaining ionic homeostasis and dynamic function in cardiac myocytes, within both the in vivo cell and in silico models. Physiological conditions differ significantly between mammalian species. However, most existing formulations of NKA used to simulate cardiac function in computational models are derived from a broad range of experimental sources spanning many animal species. The resultant inability of these models to discern species-specific features is a significant obstacle to achieving a detailed quantitative and comparative understanding of physiological behaviour in different biological contexts. Here we present a framework for characterising the steady-state NKA current using a biophysical mechanistic model specifically designed to provide a mechanistic explanation of the NKA flux supported by self-consistent species-specific data. We thus compared NKA kinetics specific to guinea- pig and rat ventricular myocytes. We observe that the apparent binding affinity for sodium in the rat is significantly lower, whereas the overall pump cycle rate is doubled, in comparison to the guinea pig. This sensitivity of NKA to its regulatory substrates compensates for the differences in Na(+) concentrations between the cell types. NKA is thereby maintained within its dynamic range over a wide range of pacing frequencies in these two species, despite significant disparities in sodium concentration. Hence, by replacing a conventional generic NKA model with our rat-specific NKA formula into a whole-cell simulation, we have, for the first time, been able to accurately reproduce the action potential duration and the steady-state sodium concentration as functions of pacing frequency.
在体内细胞和计算机模型中，钠钾ATP酶（NKA）在维持心肌细胞的离子稳态和动态功能方面发挥着关键作用。哺乳动物物种之间的生理条件存在显著差异。然而，计算模型中用于模拟心脏功能的大多数现有NKA公式都源自广泛的实验来源，涵盖了许多动物物种。这些模型无法识别物种特异性特征，这是在不同生物学背景下实现对生理行为进行详细定量和比较理解的重大障碍。在此，我们提出了一个框架，用于使用生物物理机制模型来表征稳态NKA电流，该模型专门设计用于为基于自洽的物种特异性数据支持的NKA通量提供机制解释。因此，我们比较了豚鼠和大鼠心室肌细胞特有的NKA动力学。我们观察到，与豚鼠相比，大鼠对钠的表观结合亲和力显著降低，而整体泵循环速率则增加了一倍。NKA对其调节底物的这种敏感性弥补了细胞类型之间钠浓度的差异。因此，尽管钠浓度存在显著差异，但在这两个物种中，NKA在很宽的起搏频率范围内都能维持在其动态范围内。因此，通过将我们的大鼠特异性NKA公式替换传统的通用NKA模型应用于全细胞模拟，我们首次能够准确地将动作电位持续时间和稳态钠浓度再现为起搏频率的函数。
