Ion homeostasis in the regulation of intracellular pH and volume of human erythrocytes
Abstract
Background: Cell volume maintenance by regulating the water and ion content is crucial for the survival and functional fullness of human erythrocytes. However, cells are incredibly complex systems with numerous, often competing, reactions occurring simultaneously. Hence, anticipating the overall behavior of the system or acquiring a new understanding of how the subcomponents of the system interact might pose a considerable challenge in the absence of employing mathematical modeling methods.
Objectives: Creation of a mathematical metabolic model of erythrocyte ion homeostasis to study the mechanisms of erythrocyte volume stabilization and intracellular pH in in vitro experiments.
Material and Methods: The mathematical model was developed using general approaches to modeling cellular metabolism, which are based on systems of ordinary differential equations describing metabolic reactions, passive and active ion fluxes. The generation of the model and all computations, relying on the model, were executed utilizing the COPASI 4.38 simulation environment. Changes in intracellular pH, Na+/K+-ATPase, and Ca2+-ATPase activities of donor erythrocytes incubated in saline solutions in the absence and presence of Ca2+ ions were used to test the model.
Results: The kinetic model of erythrocyte ion homeostasis was created. Using realistic parameters of the system changes over time in cell volume, concentrations of metabolites, ions fluxes and transmembrane potential were calculated. The simulation results were used to analyze the reasons for changes in the resistance to acid hemolysis of erythrocytes under the conditions of their incubation in saline solutions of different compositions.
Conclusion: We show that cation homeostasis in erythrocytes is maintained mainly by the active movement of Na+ and K+ through Na+, K+-ATPase, combined with relatively lower passive permeability through other transport pathways. In the presence of Ca2+ ions and the activation of potassium release through Gardos channels, the cell volume is stabilized due to a change in the transmembrane potential and activation of electrodiffusion ion fluxes. The study demonstrated that the reduction in acid resistance of erythrocytes during incubation in a saline solution is associated with a decrease in their cell volume, whereas the increase in acid resistance during incubation in the presence of Ca2+ ions is linked to the activation of the Na+/H+ exchanger.
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