A Simulation Study to Rescue the Na⁺/Ca²⁺ Exchanger Knockout Mice

Abstract

The Na⁺/Ca²⁺ exchanger (NCX) is the major Ca²⁺ efflux system in cardiac myocytes, and thereby its global knockout is embryonically lethal. However, Henderson et al. (2004) found that mice with the cardio-specific knockout of NCX1 lived to adulthood. No adaptation was detected in expression levels of other proteins except for 50% reduction in the L-type Ca²⁺ current (I_CaL) as revealed in electrophysiological studies. To predict mechanisms of survival, we simulated cardiac myocyte activity in the absence of NCX using a mathematical model of guinea pig ventricular myocytes. The NCX knockout resulted in contracture of the model cell due to a rise in the cytoplasmic Ca²⁺ ([Ca²⁺]_i). However, up-regulation of the sarcolemmal Ca²⁺ pump (PMCA) and/or down-regulation of I_CaL enables steady rhythmic contractions even if NCX was totally excluded. The simulation predicted that the steady activities are maintained by a functional up-regulation of PMCA by about 2.3 times in addition to the down-regulation of I_CaL to a half as observed in the experiment. However, the model analysis predicted that the myocyte depending on PMCA for Ca²⁺ extrusion is unstable against any changes in ionic fluxes and energetically unfavorable as compared with the control. The reason for the instability is that the activity of PMCA driven by the ATP hydrolysis is hardly affected by changes in [Ca²⁺]_i, while NCX has a reversal potential in the middle level of the action potential, and is immediately affected by the Ca²⁺ flux via NCX itself. The source code of the model is available at http://www.sim-bio.org/.