Genetic modulation of the SERCA activity does not affect the Ca2+ leak from the cardiac sarcoplasmic reticulum

The Ca2+ content in the sarcoplasmic reticulum (SR) determines the amount of Ca2+ released, thereby regulating the magnitude of Ca2+ transient and contraction in cardiac muscle. The Ca2+ content in the SR is known to be regulated by two factors: the activity of the Ca2+ pump (SERCA) and Ca2+ leak through the ryanodine receptor (RyR). However, the direct relationship between the SERCA activity and Ca2+ leak has not been fully investigated in the heart. In the present study, we evaluated the role of the SERCA activity in Ca2+ leak from the SR using a novel saponin-skinned method combined with transgenic mouse models in which the SERCA activity was genetically modulated. In the SERCA overexpression mice, the Ca2+ uptake in the SR was significantly increased and the Ca2+ transient was markedly increased. However, Ca2+ leak from the SR did not change significantly. In mice with overexpression of a negative regulator of SERCA, sarcolipin, the Ca2+ uptake by the SR was significantly decreased and the Ca2+ transient was markedly decreased. Again, Ca2+ leak from the SR did not change significantly. In conclusion, the selective modulation of the SERCA activity modulates Ca2+ uptake, although it does not change Ca2+ leak from the SR.