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

, , , , , , , , , , , and . 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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