Species-Specific Comparison of the Cardiac Sodium/Potassium Pump Based on a Minimal Biophysical Model

The Na+/K+ ATPase (NKA) plays a critical role in maintaining the concentration gradients, across the plasma membrane, of potassium (which determines the cell's membrane potential) and sodium, the driving force behind crucial ion-exchange processes, including calcium extraction via the sodium/calcium exchanger. This function has been extensively studied, experimentally and by computational simulations, within the context of the excitation/contraction coupling in cardiac myocytes. An important source of complexity in these strongly couple systems is the significant species-dependent variability of physiological conditions under which NKA operates, particularly the intracellular sodium concentration [Na+]i. For example, [Na+]i ∼ 11 mM in rat ventricular myocytes, and ∼ 5 mM in guinea pig. An important question is whether (1) NKA is maintained across species and operates in different species-specific regimes; or (2) NKA shows significant species-dependent variations and hence participates directly in defining physiological conditions. Most existing models neglect this fundamental question by assuming a generic NKA formulation derived from disparate experimental sources. To address this problem, we propose a biophysical framework for characterizing NKA function, specifically designed for species-specific parameterization, and produce separate models for rat and guinea pig NKA, each parameterized from fully consistent data sets. We find that the apparent binding affinity for sodium in the rat is lower by a factor of approximately three, whereas the overall pump current magnitude is roughly doubled, relative to guinea pig. These trends mirror those for the [Na+]i differences, suggesting that NKA kinetics compensates or has adapted to its physiological conditions. Such comparisons allow an analysis of the relative influence of cellular components, ionic conditions, and the action potential on ion transport in cardiac contraction, and ultimately enable the quantification of variations in physiological function of NKA across biological contexts.