Two-variable nullcline analysis of ionic general equilibrium predicts calcium homeostasis in ventricular myocytes
Fig 7
Schematics of possible SERCA gene therapy outcomes.
Schematics of how SERCA gene therapy may fail in certain cells. A) During SERCA gene therapy a sudden increase in maximum SERCA uptake does not change initially the LCC or the release but it decreases NCX function as it decreases cytosolic calcium. This necessarily leads to a state of calcium unbalance that must be rebalanced again. B) Homeostasis will always fix and rebalance the system. However, the particulars of how this is done are not universal. They depend on the nullcline structure and reaction to shocks. For instance, in a healthy rabbit, the cell increases total calcium content by increasing considerably the calcium in the SR while diminishing cytosolic calcium levels. This increase in SR calcium results in a higher transient that allows a higher extraction of calcium through the NCX, even if diastolic calcium is reduced. However, it can happen that the RyR has a weak sensitivity to SR calcium content, so release remains almost constant. Since uptake is increased, the diastolic cytosolic level has to be increased to allow calcium extrusion through the NCX, then the transient is decreased, which results in decreased contractibility despite a stronger SERCA.