Non-Technical Summary Cardiac contraction is caused by an increase of calcium (Ca2+) concentration in the cells of the heart, the so-called ‘systolic Ca2+ transient’. The majority of this Ca2+ is provided by the sarcoplasmic reticulum (SR), which acts as a Ca2+ store within the cell itself. Before the heart can contract again the Ca2+ store needs to be replenished and so Ca2+ is pumped back into the SR by the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA). We show that a given fractional decrease of SERCA activity produces a much smaller decrease of SR Ca2+ content. This means that changes of SERCA activity can produce large changes of systolic Ca2+ without the need for energetically expensive alterations of SR Ca2+ content.
Abstract Changes of the activity of the sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) affect the amplitude of the systolic Ca2+ transient and thence cardiac contractility. This is thought to be due to alterations of SR Ca2+ content. Recent work on mice in which the expression of SERCA is decreased found that a large reduction of SERCA expression resulted in a proportionately much smaller decrease of SR Ca2+ content. The aim of the current work was to investigate the quantitative nature of the dependence of both the amplitude of the systolic Ca2+ transient and SR Ca2+ content on SERCA activity during acute partial inhibition of SERCA. Experiments were performed on rat ventricular myocytes. Brief application of thapsigargin (1 μm) resulted in a decrease of SERCA activity as measured from the rate of decay of the systolic Ca2+ transient. This was accompanied by a decrease in the amplitude of the systolic Ca2+ transient which was linearly related to that of SERCA activity. However, the fractional decrease in the SR Ca2+ content was much less than that of SERCA activity. On average SR Ca2+ content was proportional to SERCA activity raised to the 0.38 ± 0.07 power. This shallow dependence of SR content on SERCA activity arises because Ca2+ release is a steep function of SR Ca2+ content. In contrast SR Ca2+ content was increased 4.59 ± 0.40 (n= 8)-fold by decreasing ryanodine receptor opening with tetracaine (1 mm). Therefore a modest decrease of SR Ca2+ content results in a proportionately larger fall of Ca2+ release from the SR which can balance a larger initiating decrease of SERCA. In conclusion, the shallow dependence of SR Ca2+ content on SERCA activity is expected for a system in which small changes of SR Ca2+ content produce larger effects on the amplitude of the systolic Ca2+ transient.