title: The effects of intracellular Ca2+ on cardiac K+ channel expression and activity: novel insights from genetically altered mice.
abstract: 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.
authors.affiliation: Division of Cardiovascular Medicine, Genome and Biomedical Sciences Facility, University of California-Davis, Rm 6315, 451 East Health Sciences Drive, Davis, CA 95616, USA.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Xu
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Valeriy
authors.initials: V
authors.lastname: Timofeyev
authors.forename: Dipika
authors.initials: D
authors.lastname: Sharma
authors.forename: Danyan
authors.initials: D
authors.lastname: Xu
authors.forename: Dipika
authors.initials: D
authors.lastname: Tuteja
authors.forename: Pei Hong
authors.initials: PH
authors.lastname: Dong
authors.forename: Gias Uddin
authors.initials: GU
authors.lastname: Ahmmed
authors.forename: Yong
authors.initials: Y
authors.lastname: Ji
authors.forename: Gary E
authors.initials: GE
authors.lastname: Shull
authors.forename: Muthu
authors.initials: M
authors.lastname: Periasamy
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
mesh_terms: 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
chemical_list: D011994:Recombinant Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases; D002118:Calcium