Changes of SERCA activity have only modest effects on sarcoplasmic reticulum Ca2+ content in rat ventricular myocytes

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 mu M) 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.