The effects of intracellular Ca$^2+$ on cardiac K$^+$ channel expression and activity: novel insights from genetically altered mice.
Y. Xu, Z. Zhang, V. Timofeyev, D. Sharma, D. Xu, D. Tuteja, P. Dong, G. Ahmmed, Y. Ji, G. Shull, M. Periasamy, and N. Chiamvimonvat.
J. Physiol. 562 (Pt 3): 745--758 (February 2005)

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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