A simulation study to rescue the Na+/Ca2+ exchanger knockout mice.
The Na(+)/Ca(2+) exchanger (NCX) is the major Ca(2+) efflux system in cardiac myocytes, and thereby its global knockout is embryonically lethal. However, Henderson et al. (2004) found that mice with the cardiospecific knockout of NCX1 lived to adulthood. No adaptation was detected in expression levels of other proteins except for a 50% reduction in the L-type Ca(2+) 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 because of a rise in the cytoplasmic Ca(2+) ([Ca(2+)](i)). However, up-regulation of the sarcolemmal Ca(2+) pump (PMCA) and/or down-regulation of I(CaL) enables steady rhythmic contractions even if NCX is 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 Ca(2+) extrusion is unstable against any changes in ionic fluxes and energetically unfavorable in comparison 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 [Ca(2+)](i), but NCX has a reversal potential in the middle level of the action potential and is immediately affected by the Ca(2+) flux via NCX itself. The source code of the model is available at http://www.sim-bio.org/.
Sarai
Nobuaki
N
Department of Physiology and Biophysics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. sarai@card.med.kyoto-u.ac.jp
Kobayashi
Tsutomu
T
Matsuoka
Satoshi
S
Noma
Akinori
A
D000200:Action Potentials / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology; D004594:Electrophysiology; D006168:Guinea Pigs; D006868:Hydrolysis; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008962:Models, Theoretical; D032383:Myocytes, Cardiac / Q000502:physiology; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D012508:Sarcolemma / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000235:genetics* / Q000502:physiology*; D015854:Up-Regulation
D020746:Calcium Channels, L-Type; C499849:NCX1 protein, mouse; D019831:Sodium-Calcium Exchanger; D000255:Adenosine Triphosphate; D053499:Plasma Membrane Calcium-Transporting ATPases; D002118:Calcium