CaMKIIδ isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses

Tong Zhang, Michael Kohlhaas, Johannes Backs, Shikha Mishra, William Phillips, Nataliya Dybkova, Shurong Chang, Haiyun Ling, Donald M. Bers, Lars S. Maier, Eric N. Olson, Joan Heller Brown

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Abstract

The δB and δC splice variants of Ca 2+/calmodulin-dependent protein kinase II (CaMKII), which differ by the presence of a nuclear localization sequence, are both expressed in cardiomyocytes. We used transgenic (TG) mice and CaMKII expression in cardiomyocytes to test the hypothesis that the CaMKIIδC isoform regulates cytosolic Ca2+ handling and the δB isoform, which localizes to the nucleus, regulates gene transcription. Phosphorylation of CaMKII sites on the ryanodine receptor (RyR) and on phospholamban (PLB) were increased in CaMKIIδC TG. This was associated with markedly enhanced sarcoplasmic reticulum (SR) Ca2+ spark frequency and decreased SR Ca2+ content in cardiomyocytes. None of these parameters were altered in TG mice expressing the nuclear-targeted CaMKIIδB. In contrast, cardiac expression of either CaMKIIδB or δC induced transactivation of myocyte enhancer factor 2 (MEF2) gene expression and up-regulated hypertrophic marker genes. Studies using rat ventricular cardiomyocytes confirmed that CaMKIIδB and δC both regulate MEF2-luciferase gene expression, increase histone deacetylase 4 (HDAC4) association with 14-3-3, and induce HDAC4 translocation from nucleus to cytoplasm, indicating that either isoform can stimulate HDAC4 phosphorylation. Finally, HDAC4 kinase activity was shown to be increased in cardiac homogenates from either CaMKIIδB or δC TG mice. Thus CaMKIIδ isoforms have similar effects on hypertrophic gene expression but disparate effects on Ca2+ handling, suggesting distinct roles for CaMKIIδ isoform activation in the pathogenesis of cardiac hypertrophy versus heart failure.

Original languageEnglish (US)
Pages (from-to)35078-35087
Number of pages10
JournalJournal of Biological Chemistry
Volume282
Issue number48
DOIs
StatePublished - Nov 30 2007

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MEF2 Transcription Factors
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Protein Isoforms
Cardiac Myocytes
Histone Deacetylases
Calcium
Gene expression
Transgenic Mice
Phosphorylation
Sarcoplasmic Reticulum
Gene Expression
Genes
Calcium-Calmodulin-Dependent Protein Kinases
Ryanodine Receptor Calcium Release Channel
Cardiomegaly
Transcription
Luciferases
Electric sparks
Transcriptional Activation
Rats

ASJC Scopus subject areas

  • Biochemistry

Cite this

Zhang, T., Kohlhaas, M., Backs, J., Mishra, S., Phillips, W., Dybkova, N., ... Brown, J. H. (2007). CaMKIIδ isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses. Journal of Biological Chemistry, 282(48), 35078-35087. https://doi.org/10.1074/jbc.M707083200

CaMKIIδ isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses. / Zhang, Tong; Kohlhaas, Michael; Backs, Johannes; Mishra, Shikha; Phillips, William; Dybkova, Nataliya; Chang, Shurong; Ling, Haiyun; Bers, Donald M.; Maier, Lars S.; Olson, Eric N.; Brown, Joan Heller.

In: Journal of Biological Chemistry, Vol. 282, No. 48, 30.11.2007, p. 35078-35087.

Research output: Contribution to journalArticle

Zhang, T, Kohlhaas, M, Backs, J, Mishra, S, Phillips, W, Dybkova, N, Chang, S, Ling, H, Bers, DM, Maier, LS, Olson, EN & Brown, JH 2007, 'CaMKIIδ isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses', Journal of Biological Chemistry, vol. 282, no. 48, pp. 35078-35087. https://doi.org/10.1074/jbc.M707083200
Zhang, Tong ; Kohlhaas, Michael ; Backs, Johannes ; Mishra, Shikha ; Phillips, William ; Dybkova, Nataliya ; Chang, Shurong ; Ling, Haiyun ; Bers, Donald M. ; Maier, Lars S. ; Olson, Eric N. ; Brown, Joan Heller. / CaMKIIδ isoforms differentially affect calcium handling but similarly regulate HDAC/MEF2 transcriptional responses. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 48. pp. 35078-35087.
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AU - Kohlhaas, Michael

AU - Backs, Johannes

AU - Mishra, Shikha

AU - Phillips, William

AU - Dybkova, Nataliya

AU - Chang, Shurong

AU - Ling, Haiyun

AU - Bers, Donald M.

AU - Maier, Lars S.

AU - Olson, Eric N.

AU - Brown, Joan Heller

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N2 - The δB and δC splice variants of Ca 2+/calmodulin-dependent protein kinase II (CaMKII), which differ by the presence of a nuclear localization sequence, are both expressed in cardiomyocytes. We used transgenic (TG) mice and CaMKII expression in cardiomyocytes to test the hypothesis that the CaMKIIδC isoform regulates cytosolic Ca2+ handling and the δB isoform, which localizes to the nucleus, regulates gene transcription. Phosphorylation of CaMKII sites on the ryanodine receptor (RyR) and on phospholamban (PLB) were increased in CaMKIIδC TG. This was associated with markedly enhanced sarcoplasmic reticulum (SR) Ca2+ spark frequency and decreased SR Ca2+ content in cardiomyocytes. None of these parameters were altered in TG mice expressing the nuclear-targeted CaMKIIδB. In contrast, cardiac expression of either CaMKIIδB or δC induced transactivation of myocyte enhancer factor 2 (MEF2) gene expression and up-regulated hypertrophic marker genes. Studies using rat ventricular cardiomyocytes confirmed that CaMKIIδB and δC both regulate MEF2-luciferase gene expression, increase histone deacetylase 4 (HDAC4) association with 14-3-3, and induce HDAC4 translocation from nucleus to cytoplasm, indicating that either isoform can stimulate HDAC4 phosphorylation. Finally, HDAC4 kinase activity was shown to be increased in cardiac homogenates from either CaMKIIδB or δC TG mice. Thus CaMKIIδ isoforms have similar effects on hypertrophic gene expression but disparate effects on Ca2+ handling, suggesting distinct roles for CaMKIIδ isoform activation in the pathogenesis of cardiac hypertrophy versus heart failure.

AB - The δB and δC splice variants of Ca 2+/calmodulin-dependent protein kinase II (CaMKII), which differ by the presence of a nuclear localization sequence, are both expressed in cardiomyocytes. We used transgenic (TG) mice and CaMKII expression in cardiomyocytes to test the hypothesis that the CaMKIIδC isoform regulates cytosolic Ca2+ handling and the δB isoform, which localizes to the nucleus, regulates gene transcription. Phosphorylation of CaMKII sites on the ryanodine receptor (RyR) and on phospholamban (PLB) were increased in CaMKIIδC TG. This was associated with markedly enhanced sarcoplasmic reticulum (SR) Ca2+ spark frequency and decreased SR Ca2+ content in cardiomyocytes. None of these parameters were altered in TG mice expressing the nuclear-targeted CaMKIIδB. In contrast, cardiac expression of either CaMKIIδB or δC induced transactivation of myocyte enhancer factor 2 (MEF2) gene expression and up-regulated hypertrophic marker genes. Studies using rat ventricular cardiomyocytes confirmed that CaMKIIδB and δC both regulate MEF2-luciferase gene expression, increase histone deacetylase 4 (HDAC4) association with 14-3-3, and induce HDAC4 translocation from nucleus to cytoplasm, indicating that either isoform can stimulate HDAC4 phosphorylation. Finally, HDAC4 kinase activity was shown to be increased in cardiac homogenates from either CaMKIIδB or δC TG mice. Thus CaMKIIδ isoforms have similar effects on hypertrophic gene expression but disparate effects on Ca2+ handling, suggesting distinct roles for CaMKIIδ isoform activation in the pathogenesis of cardiac hypertrophy versus heart failure.

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