Characterization of the cardiac Na+/K+ pump by development of a comprehensive and mechanistic model.
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 (I(NaK)), 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-I(NaK) 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-I(NaK) 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.
Oka
Chiaki
C
Cell/Biodynamics Simulation Project, Kyoto University, Kyoto, Japan.
Cha
Chae Young
CY
Noma
Akinori
A
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004560:Electricity; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D015640:Ion Channel Gating; D007477:Ions / Q000378:metabolism; D008954:Models, Biological; D009206:Myocardium / Q000201:enzymology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*
D007477:Ions; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000254:Sodium-Potassium-Exchanging ATPase