The effects of intracellular Ca2+ on cardiac K+ channel expression and activity:: novel insights from genetically altered mice

We tested the hypothesis that chronic changes in intracellular Ca2+ (Ca-i(2+)) can result in changes in ion channel expression; this represents a novel mechanism of crosstalk between changes in Ca2+ cycling proteins and the cardiac action potential (AP) profile. We used a transgenic mouse with cardiac-specific overexpression of sarcoplasmic reticulum Ca2+ ATPase (SERCA) isoform Ia (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,I-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 SERCA I a OE mice. The electrophysiological changes, which correlated with changes in Ca-i(2+), were further corroborated by measuring the levels of ion channel protein expression. To recapitulate the in vivo experiments, the effects of changes in Ca-i(2+) on ion channel expression were further tested in cultured adult and neonatal mouse cardiac myocytes. We conclude that a primary defect in Ca2+ handling proteins without cardiac hypertrophy or failure may produce profound changes in K+ channel expression and activity as well as cardiac AP.