Sarcoplasmic reticulum Ca²⁺ ATPase (SERCA) 1a structurally substitutes for SERCA2a in the cardiac sarcoplasmic reticulum and increases cardiac Ca²⁺ handling capacity

Ectopic expression of the sarcoplasmic reticulum (SR) Ca²⁺ ATPase (SERCA) 1a pump in the mouse heart results in a 2.5-fold increase in total SERCA pump level. SERCA 1a hearts show increased rates of contraction/relaxation and enhanced Ca²⁺ transients; however, the cellular mechanisms underlying altered Ca²⁺ handling in SERCA1a transgenic (TG) hearts are unknown. In this study, using confocal microscopy, we demonstrate that SERCA1a protein traffics to the cardiac SR and structurally substitutes for the endogenous SERCA2a isoform. SR Ca²⁺ load measurements revealed that TG myocytes have significantly enhanced SR Ca²⁺ load. Confocal line-scan images of field-stimulated SR Ca²⁺ release showed an increased rate of Ca²⁺ removal in TG myocytes. On the other hand, ryanodine receptor binding activity was decreased by ≈30%. However, TG myocytes had a greater rate of spontaneous ryanodine receptor opening as measured by spark frequency. Whole-cell L-type Ca²⁺ current density was reduced by ≈50%, whereas the time course of inactivation was unchanged in TG myocytes. These studies provide important evidence that SERCA1a can substitute both structurally and functionally for SERCA2a in the heart and that SERCA1a overexpression can be used to enhance SR Ca²⁺ transport and cardiac contractility.