Regulation of sarcoplasmic reticulum Ca 2+ leak by cytosolic Ca 2+ in rabbit ventricular myocytes

Non‐technical summary  Contraction and relaxation of the heart strongly depend on calcium (Ca 2+ ) stored in the sarcoplasmic reticulum (SR). Ca 2+ stored within the SR is determined by the balance between Ca 2+ uptake and Ca 2+ leak that occurs mainly via Ca 2+ release channels, called ryanodine receptors (RyRs). Alterations in the RyR activity can lead to enhanced SR Ca 2+ leak and arrhythmias. Ca 2+ tightly regulates the RyR activity from both sides of the SR (cytosolic and luminal). In this work, we studied the effects of cytosolic Ca 2+ on SR Ca 2+ leak in isolated ventricular myocytes. Elevation of cytosolic Ca 2+ increased SR Ca 2+ leak by a direct activation of RyRs. In intact myocytes, at the end of contraction and at the beginning of the relaxation phase, SR Ca 2+ leak remains relatively constant due to the coordinated regulation of RyRs by cytosolic and luminal Ca 2+ . Thus, this dual regulation of the RyR contributes to the control of the SR Ca 2+ content, preventing excessive loss of Ca 2+ that could lead to pathological conditions such as cardiac arrhythmia.