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2 Division of Cardiovascular Medicine, University of California, Davis, Davis, CA
6 Department of Veterans Affairs, Northern California Health Care System, Mather, CA
5 Department of Physiology and Cell Biology, Ohio State University, Columbus, OH
3 Department of Internal Medicine
4 Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Cincinnati, OH, USA
1 Pharmacology Department, Hebei Medical University Shijiazhuang, China
We tested the hypothesis that chronic changes in intracellular Ca2+ (Ca2+i) 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 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 (Ito,f), a slowly inactivating K+ current (IK,slow) and the steady state current (ISS) 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 Ca2+i, were further corroborated by measuring the levels of ion channel protein expression. To recapitulate the in vivo experiments, the effects of changes in Ca2+i 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.
(Received 28 September 2004;
accepted after revision 19 November 2004;
first published online 25 November 2004)
Corresponding author N. Chiamvimonvat: Division of Cardiovascular Medicine, University of California, Davis, Genome and Biomedical Sciences Facility, Rm 6315, 451 East Health Sciences Drive, Davis, CA 95616, USA. Email: nchiamvimonvat{at}ucdavis.edu
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