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A simulation study to rescue the Na+/Ca2+ exchanger knockout mice
Nobuaki Sarai1, Tsutomu Kobayashi, Satoshi Matsuoka
1Department of Physiology and Biophysics, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. sarai@card.med.kyoto-u.ac.jp
Abstract:
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/.
Insights
Cardiac-specific knockout of the sodium-calcium exchanger (NCX) allows survival by upregulating the sarcolemmal calcium pump (PMCA) and reducing L-type calcium current (ICaL). However, this compensatory mechanism creates an unstable and energetically unfavorable cellular environment.
Area of Science:
- Cardiovascular Physiology
- Computational Biology
- Molecular Cardiology
Background:
- The Na(+)/Ca(2+) exchanger (NCX) is crucial for Ca(2+) extrusion in cardiac myocytes, with global knockout proving embryonically lethal.
- Cardiospecific knockout of NCX1 allows adult survival, with observed adaptations including a 50% reduction in L-type Ca(2+) current (ICaL).
Purpose of the Study:
- To predict the mechanisms enabling survival in cardiac myocytes lacking functional NCX.
- To investigate the compensatory roles of other Ca(2+) handling proteins and currents.
Main Methods:
- Utilized a mathematical model of guinea pig ventricular myocytes to simulate cellular activity.
- Simulated the absence of NCX and analyzed the impact on cytoplasmic Ca(2+) ([Ca(2+)](i)) and cellular contractility.
- Assessed the effects of altered sarcolemmal Ca(2+) pump (PMCA) activity and ICaL levels.
Main Results:
- NCX knockout initially caused contracture due to elevated [Ca(2+)](i).
- Simulations predicted that combined PMCA upregulation (approx. 2.3x) and ICaL downregulation (to 50%) enable steady rhythmic contractions.
- Model analysis indicated that PMCA-dependent Ca(2+) extrusion leads to instability and is energetically unfavorable compared to NCX-mediated extrusion.
Conclusions:
- Survival in NCX-deficient cardiac myocytes relies on significant PMCA upregulation and ICaL reduction.
- PMCA-based Ca(2+) extrusion is less stable and energetically efficient than NCX due to differing sensitivities to ionic flux and membrane potential.
- The study highlights the complex interplay of ion transport systems in maintaining cardiac myocyte function under altered conditions.
