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.

URL: http://dx.doi.org/10.1113/jphysiol.2004.076216
DOI: 10.1113/jphysiol.2004.076216
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@article{Xu_2005_745,
  abstract = {We tested the hypothesis that chronic changes in intracellular {C}a$^{2+}$
	({C}a$^{2+}$(i)) can result in changes in ion channel expression;
	this represents a novel mechanism of crosstalk between changes in
	{C}a$^{2+}$ cycling proteins and the cardiac action potential (AP)
	profile. We used a transgenic mouse with cardiac-specific overexpression
	of sarcoplasmic reticulum {C}a$^{2+}$ 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
	{C}a$^{2+}$(i), were further corroborated by measuring the levels
	of ion channel protein expression. To recapitulate the in vivo experiments,
	the effects of changes in {C}a$^{2+}$(i) on ion channel expression
	were further tested in cultured adult and neonatal mouse cardiac
	myocytes. We conclude that a primary defect in {C}a$^{2+}$ handling
	proteins without cardiac hypertrophy or failure may produce profound
	changes in {K}$^{+}$ channel expression and activity as well as cardiac
	AP.},
  added-at = {2009-06-03T11:20:58.000+0200},
  author = {Xu, Yanfang and Zhang, Zhao and Timofeyev, Valeriy and Sharma, Dipika and Xu, Danyan and Tuteja, Dipika and Dong, Pei Hong and Ahmmed, Gias Uddin and Ji, Yong and Shull, Gary E and Periasamy, Muthu and Chiamvimonvat, Nipavan},
  biburl = {https://www.bibsonomy.org/bibtex/21b3f8536816c3f781568f221f6f2bc21/hake},
  description = {The whole bibliography file I use.},
  doi = {10.1113/jphysiol.2004.076216},
  file = {Xu_2005_745.pdf:Xu_2005_745.pdf:PDF},
  interhash = {f0c374e8f63f570329affc719c426381},
  intrahash = {1b3f8536816c3f781568f221f6f2bc21},
  journal = {J. Physiol.},
  keywords = {, 15564282 ATPase, Acid Action Activation, Amino Animals, Atria, Calcium, Calcium-Activated, Cardiac, Cells, Channel Channels, Comparative Cultured, Data, Electrocardiography, Enzyme Enzymologic, Expression Extramural, Fluid, Gating, Gene Gov't, Heart Intracellular Ion Male, Mice, Molecular Muscle Myocytes, N.I.H., Non-P.H.S., Non-U.S. P.H.S., Potassium Potentials, Proteins, Recombinant Regulation, Research Sequence Sequence, Study, Support, Transgenic, U.S. Ventricles, {C}a$^{2+}$-Transporting},
  month = Feb,
  number = {Pt 3},
  pages = {745--758},
  pii = {jphysiol.2004.076216},
  pmid = {15564282},
  timestamp = {2009-06-03T11:21:38.000+0200},
  title = {The effects of intracellular {C}a$^{2+}$ on cardiac {K}$^{+}$ channel
	expression and activity: novel insights from genetically altered
	mice.},
  url = {http://dx.doi.org/10.1113/jphysiol.2004.076216},
  volume = 562,
  year = 2005
}

%0 Journal Article
%1 Xu_2005_745
%A Xu, Yanfang
%A Zhang, Zhao
%A Timofeyev, Valeriy
%A Sharma, Dipika
%A Xu, Danyan
%A Tuteja, Dipika
%A Dong, Pei Hong
%A Ahmmed, Gias Uddin
%A Ji, Yong
%A Shull, Gary E
%A Periasamy, Muthu
%A Chiamvimonvat, Nipavan
%D 2005
%J J. Physiol.
%K , 15564282 ATPase, Acid Action Activation, Amino Animals, Atria, Calcium, Calcium-Activated, Cardiac, Cells, Channel Channels, Comparative Cultured, Data, Electrocardiography, Enzyme Enzymologic, Expression Extramural, Fluid, Gating, Gene Gov't, Heart Intracellular Ion Male, Mice, Molecular Muscle Myocytes, N.I.H., Non-P.H.S., Non-U.S. P.H.S., Potassium Potentials, Proteins, Recombinant Regulation, Research Sequence Sequence, Study, Support, Transgenic, U.S. Ventricles, {C}a$^{2+}$-Transporting
%N Pt 3
%P 745--758
%R 10.1113/jphysiol.2004.076216
%T The effects of intracellular Ca$^2+$ on cardiac K$^+$ channel
	expression and activity: novel insights from genetically altered
	mice.
%U http://dx.doi.org/10.1113/jphysiol.2004.076216
%V 562
%X 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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