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 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.
Xu
Yanfang
Y
Division of Cardiovascular Medicine, Genome and Biomedical Sciences Facility, University of California-Davis, Rm 6315, 451 East Health Sciences Drive, Davis, CA 95616, USA.
Zhang
Zhao
Z
Timofeyev
Valeriy
V
Sharma
Dipika
D
Xu
Danyan
D
Tuteja
Dipika
D
Dong
Pei Hong
PH
Ahmmed
Gias Uddin
GU
Ji
Yong
Y
Shull
Gary E
GE
Periasamy
Muthu
M
Chiamvimonvat
Nipavan
N
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004562:Electrocardiography; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D015640:Ion Channel Gating / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic / Q000378:metabolism*; D032342:Muscle Cells / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
D011994:Recombinant Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium