How energy shortage alters the kinetics of Na+/K+ pump and pump-mediated cellular functions?

Abstract

Disturbances in the energy balance between demand and supply in cardiac muscle alters the kinetics of Na⁺/K⁺ pump because the Na⁺/K⁺ pump is powered by ATP. Although the change of the pump activity affects various cellular functions, such as membrane excitation, contraction, volume regulation, intracellular [Ca²⁺] and pH regulation, the relationship between free energy of ATP hydrolysis (dG_ATP) and pump-mediated cellular functions is not fully understood especially in quantitative aspects. In this study, we aimed at understanding this relationship quantitatively by computational approach. First, we developed the Na⁺/K⁺ pump model by adding key experimental findings to the Smith-Crampin model, in which ion transport is coupled to dG_ATP. Our model successfully reproduces a variety of electrophysiological characteristics of Na⁺/K⁺ pump, including the dependence on [Na⁺]_i and [K⁺]_o as well as the current-voltage relationship under various ionic conditions. By using ventricular cell model, in which the new Na⁺/K⁺ model was incorporated, we induced the energy shortage condition by inhibiting NADH synthesis rate of mitochondria. This resulted in an increase of [Na⁺]_i together with an increase in metabolites ([ADP] and [Pi]). When the inhibitory effect of metabolite accumulation on the Na⁺/K⁺ pump activity became more than the compensatory effect of [Na⁺]_i increase, an irreversible increase in [Na⁺]_i was observed. We will discuss the cellular mechanisms responsible for irreversible [Na⁺]_i accumulation. [J Physiol Sci. 2007;57 Suppl:S197]