Key result
Cardiac-specific overexpression of SERCA1a in mice significantly prolonged cardiac action potential duration and QT interval, correlating with changes in K+ channel expression.
Primary defects in Ca2+ handling proteins can produce profound changes in K+ channel expression and cardiac action potentials independent of cardiac hypertrophy or failure.
Hypothesis-generating in mice; leaves open whether Ca2+ handling alters human ion channel expression or arrhythmias.
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.
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Xu et al. (2004) studied this question. Cardiac-specific overexpression of SERCA1a vs. Wild-type littermates was evaluated on Expression of K+ currents, cardiac action potential duration, and QT interval. Cardiac-specific overexpression of SERCA1a in mice significantly prolonged cardiac action potential duration and QT interval, correlating with changes in K+ channel expression.
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