Theoretical analysis of the regulation of calcium content in the rat cardiac myocyte



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Texas Tech University


In mammalian heart, the processes of excitation-contraction (E-C) coupling and Ca-induced Ca release (CICR) depend on the amount of Ca stored in the sarcoplasmic reticulum (SR). Thus the mechanisms controlling the SR Ca load are of importance for our understanding of cardiac performance. It is proposed that the SR Ca release channels activated by luminal Ca provide an adjustable Ca leak pathway, through which the SR can self-regulate its load and maintain stable CICR. It is also proposed that the diastolic fluxes (i.e. Ca fluxes circulating between the sarcoplasmic reticulum and the cytosol in the interval between heart beats) play an important role in Ca regulation. It follows from this proposal that leak from the SR, not uptake into the SR, controls the SR load.

With the help of the permeabilized myocyte model, we simulated the effects of changes in SR calcium content on the SR release, both with and without the luminal sensor mechanism during pharmacological interventions of thapsigargin. phosphorylation of phospholamban, tetracaine and caffeine. We then simulated the effects of diastolic fluxes and the luminal sensor mechanism during the tetracaine intervention on the Ca content using a whole-cell Ca dynamics model. Finally, the dominant SR regulatory mechanisms were investigated by carrying out parametric analysis using the permeabilized and the whole-cell myocyte model.

Results indicate that the luminal sensor mechanism and the diastolic fluxes accelerate the dynamics of self-regulation during intervention. The presence of the luminal sensor mechanism functions to resist excursions in SR load. Therefore the luminal sensor would be an advantageous control element from a teleological standpoint by providing additional stability to SR Ca dynamics. The flux mechanisms (sarcolemmal pump, forward SR pump, and leak) play dominant roles in SR regulation whereas the contribution due to the reverse pump mode of the SR CaATPase is negligible.

These findings have implications for the treatment of cardiac diseases by suggesting potential protein targets for pharmacotherapies and gene therapies.



Muscle cells, Rats, Heart, Calcium