Characterization of the cardiac Na/K pump by development of a comprehensive and mechanistic model |
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Authors: | Chiaki Oka Chae Young Cha Akinori Noma |
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Institution: | a Cell/Biodynamics Simulation Project, Kyoto University, Kyoto, Japan b Biosimulation Project, Faculty of Bioinformatics, College of Life Sciences, Ritsumeikan University, Noji Higashi 1-1-1, Kusatsu-City, Shiga-prefecture 525-8577, Japan |
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Abstract: | A large amount of experimental data on the characteristics of the cardiac Na+/K+ pump have been accumulated, but it remains difficult to predict the quantitative contribution of the pump in an intact cell because most measurements have been made under non-physiological conditions. To extrapolate the experimental findings to intact cells, we have developed a comprehensive Na+/K+ pump model based on the thermodynamic framework (Smith and Crampin, 2004) of the Post-Albers reaction cycle combined with access channel mechanisms. The new model explains a variety of experimental results for the Na+/K+ pump current (INaK), including the dependency on the concentrations of Na+ and K+, the membrane potential and the free energy of ATP hydrolysis. The model demonstrates that both the apparent affinity and the slope of the substrate-INaK relationship measured experimentally are affected by the composition of ions in the extra- and intracellular solutions, indirectly through alteration in the probability distribution of individual enzyme intermediates. By considering the voltage dependence in the Na+- and K+-binding steps, the experimental voltage-INaK relationship could be reconstructed with application of experimental ionic compositions in the model, and the view of voltage-dependent K+ binding was supported. Re-evaluation of charge movements accompanying Na+ and K+ translocations gave a reasonable number for the site density of the Na+/K+ pump on the membrane. The new model is relevant for simulation of cellular functions under various interventions, such as depression of energy metabolism. |
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Keywords: | Cardiac Na/K pump Computer model Na/K pump current Turnover rate |
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