The effects of intracellular Ca 2+ on cardiac K + channel expression and activity: novel insights from genetically altered mice

We tested the hypothesis that chronic changes in intracellular Ca 2+ (Ca 2+ i ) can result in changes in ion channel expression; this represents a novel mechanism of crosstalk between changes in Ca 2+ cycling proteins and the cardiac action potential (AP) profile. We used a transgenic mouse with cardiac‐specific overexpression of sarcoplasmic reticulum Ca 2+ ATPase (SERCA) isoform 1a (SERCA1a OE) with a significant alteration of SERCA protein levels without cardiac hypertrophy or failure. Here, we report significant changes in the expression of a transient outward K + current ( I to,f ), a slowly inactivating K + current ( I K,slow ) and the steady state current ( I SS ) in the transgenic mice with resultant prolongation in cardiac action potential duration (APD) compared with the wild‐type littermates. In addition, there was a significant prolongation of the QT interval on surface electrocardiograms in SERCA1a OE mice. The electrophysiological changes, which correlated with changes in Ca 2+ i , were further corroborated by measuring the levels of ion channel protein expression. To recapitulate the in vivo experiments, the effects of changes in Ca 2+ i on ion channel expression were further tested in cultured adult and neonatal mouse cardiac myocytes. We conclude that a primary defect in Ca 2+ handling proteins without cardiac hypertrophy or failure may produce profound changes in K + channel expression and activity as well as cardiac AP.