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Species‐dependent adaptation of the cardiac Na + /K + pump kinetics to the intracellular Na + concentration
Author(s) -
Lewalle Alexandre,
Niederer Steven A.,
Smith Nicolas P.
Publication year - 2014
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2014.279810
Subject(s) - biophysics , sodium , kinetics , steady state (chemistry) , intracellular , myocyte , flux (metallurgy) , chemistry , in vivo , biochemistry , biology , physics , microbiology and biotechnology , organic chemistry , quantum mechanics
Key Points The sodium/potassium pump is a membrane protein that maintains the Na + and K + concentration gradients across the plasma membrane and is therefore a key component of the cardiac contraction mechanism. Numerical models of the pump provide insight into its physiological role but most existing models neglect the significant known quantitative differences in pump kinetics between different species. We developed a biophysical mechanistic modelling framework, designed specifically to enable a fully consistent species‐specific characterisation of the pump function. We applied this framework to generate two separate species‐specific models, for the guinea pig and rat, and compared their respective kinetics in terms of objectively characterised biophysical parameters. We incorporated our rat‐specific Na + /K + ATPase model into a whole‐cell simulation and, for the first time, were able to reproduce measurements of the steady‐state intracellular sodium concentration as a function of pacing frequency.Abstract 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.