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J. Biol. Chem., Vol. 282, Issue 48, 35078-35087, November 30, 2007

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CaMKII Isoforms Differentially Affect Calcium Handling but Similarly Regulate HDAC/MEF2 Transcriptional Responses^*

Tong Zhang, Supported by a Scientist Development Grant from American Heart Association¹, Michael Kohlhaas, Johannes Backs^¶, Shikha Mishra^**2, William Phillips, Nataliya Dybkova, Shurong Chang^¶, Haiyun Ling, Donald M. Bers^||, Lars S. Maier, Eric N. Olson^¶, and Joan Heller Brown³

From the Department of Pharmacology and ^**Biomedical Sciences Graduate Program, University of California, San Diego, La Jolla, California 92093, the Abt. Kardiologie & Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, 37075 Göttingen, Germany, the ^¶Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Texas 75390, and the ^||Department of Physiology, Loyola University Chicago, Maywood, Illinois 60153

The _B and _C splice variants of Ca²⁺/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 CaMKII_C isoform regulates cytosolic Ca²⁺ handling and the _B 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 CaMKII_C 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 CaMKII_B. In contrast, cardiac expression of either CaMKII_B or _C induced transactivation of myocyte enhancer factor 2 (MEF2) gene expression and up-regulated hypertrophic marker genes. Studies using rat ventricular cardiomyocytes confirmed that CaMKII_B and _C 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 CaMKII_B or _C TG mice. Thus CaMKII isoforms have similar effects on hypertrophic gene expression but disparate effects on Ca²⁺ handling, suggesting distinct roles for CaMKII isoform activation in the pathogenesis of cardiac hypertrophy versus heart failure.

Received for publication, August 23, 2007 , and in revised form, October 4, 2007.

^* This work was supported in part by National Institutes of Health Grants HL46345 (to J. H. B.) and HL80101 (to J. H. B. and D. M. B.), DFG Grants MA1982/1-4&KFO155TP5 (to L. S. M.) and a contract grant from Scios, Inc. (to J. H. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

² Supported by Pharmacological Sciences Training Grant GM007752.

¹ To whom correspondence may be addressed: Arena Pharmaceuticals, Inc., 6166 Nancy Ridge Dr., San Diego, CA 92121. E-mail: tzhang{at}arenapharm.com. ³ To whom correspondence may be addressed: Dept. of Pharmacology, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0636. Tel.: 858-534-2595; Fax: 858-822-0041; E-mail: jhbrown{at}ucsd.edu.

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