The cardiac sarcoplasmic reticulum phospholamban kinase is a distinct δ‐CaM kinase isozyme

Baltas, Leonidas G.; Karczewski, Peter; Krause, Ernst‐Georg

doi:10.1016/0014-5793(95)00981-e

Cited by 55 publications

(44 citation statements)

References 35 publications

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“…CaMKII is encoded by 4 genes (Camk2a, Camk2b, Camk2d, and Camk2g), of which the δ and γ isoforms are expressed in heart (22), with δ as the predominant isoform (23)(24)(25)(26). Accordingly, we set out to generate mice in which the CaMKIIδ isoform was genetically deleted.…”

Section: Introductionmentioning

confidence: 99%

Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice

Ling¹,

Zhang²,

Pereira³

et al. 2009

J. Clin. Invest.

343

267

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Ca 2+ /calmodulin-dependent kinase II (CaMKII) has been implicated in cardiac hypertrophy and heart failure. We generated mice in which the predominant cardiac isoform, CaMKIIδ, was genetically deleted (KO mice), and found that these mice showed no gross baseline changes in ventricular structure or function. In WT and KO mice, transverse aortic constriction (TAC) induced comparable increases in relative heart weight, cell size, HDAC5 phosphorylation, and hypertrophic gene expression. Strikingly, while KO mice showed preserved hypertrophy after 6-week TAC, CaMKIIδ deficiency significantly ameliorated phenotypic changes associated with the transition to heart failure, such as chamber dilation, ventricular dysfunction, lung edema, cardiac fibrosis, and apoptosis. The ratio of IP 3 R2 to ryanodine receptor 2 (RyR2) and the fraction of RyR2 phosphorylated at the CaMKII site increased significantly during development of heart failure in WT mice, but not KO mice, and this was associated with enhanced Ca 2+ spark frequency only in WT mice. We suggest that CaMKIIδ contributes to cardiac decompensation by enhancing RyR2-mediated sarcoplasmic reticulum Ca 2+ leak and that attenuating CaMKIIδ activation can limit the progression to heart failure.

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Section: Introductionmentioning

confidence: 99%

Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice

Ling¹,

Zhang²,

Pereira³

et al. 2009

J. Clin. Invest.

343

267

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“…18 Members of the CaMKII ␦-class represent the best characterized cardiac CaMKII isoforms. 8,9,19,20 At the beginning of this study, from the known ␦-isoforms (termed ␦ 1 through ␦ 10 according to Mayer et al 9 ), the presence of proteins for isoforms ␦ 2 , ␦ 3 , and probably ␦ 9 has been demonstrated in cardiac tissue. 19 -21 Isoform ␦ 3 , which contains a functional nuclear localization signal in its variable domain I, may be involved in the regulation of atrial natriuretic factor (ANF) gene expression 13 and appears to be a dominant isoform in the adult heart.…”

Section: T He Camentioning

confidence: 87%

Identification and Expression of δ-Isoforms of the Multifunctional Ca ²⁺ /Calmodulin-Dependent Protein Kinase in Failing and Nonfailing Human Myocardium

Hoch

Meyer

Hetzer

et al. 1999

Circulation Research

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302

242

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Abstract-Despite its importance for the regulation of heart function, little is known about the isoform expression of the multifunctional Ca 2ϩ /calmodulin-dependent protein kinase (CaMKII) in human myocardium. In this study, we investigated the spectrum of CaMKII isoforms ␦ 2 , ␦ 3 , ␦ 4 , ␦ 8 , and ␦ 9 in human striated muscle tissue. Isoform ␦ 3 is characteristically expressed in cardiac muscle. In skeletal muscle, specific expression of a new isoform termed ␦ 11 is demonstrated. Complete sequencing of human ␦ 2 cDNA, representing all common features of the investigated CaMKII subclass, revealed its high homology to the corresponding rat cDNA. Comparative semiquantitative reverse transcription-polymerase chain reaction analyses from left ventricular tissues of normal hearts and from patients suffering from dilated cardiomyopathy showed a significant increase in transcript levels of isoform ␦ 3 relative to the expression of glyceraldehyde-3-phosphate dehydrogenase in diseased hearts (101.6Ϯ11.0% versus 64.9Ϯ9.9% in the nonfailing group; PϽ0.05, nϭ6). Transcript levels of the other investigated cardiac CaMKII isoforms remained unchanged. At the protein level, by using a subclass-specific antibody, we observed a similar increase of a ␦-CaMKII-specific signal (7.2Ϯ1.0 versus 3.8Ϯ0.7 optical density units in the nonfailing group; PϽ0.05, nϭ4 through 6). The diseased state of the failing hearts was confirmed by a significant increase in transcript levels for atrial natriuretic peptide (292.9Ϯ76.4% versus 40.1Ϯ3.2% in the nonfailing group; PϽ0.05, nϭ3 through 6). Our data characterize for the first time the ␦-CaMKII isoform expression pattern in human hearts and demonstrate changes in this expression pattern in heart failure. (Circ Res. 1999;84:713-721.)

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“…CaMKII is a homo-or heteromultimer of 6 -12 subunits encoded by ␣, ␤, ␥, or ␦ genes (33,34). The ␦ subunit of CaMKII predominates in the heart and there are distinct splice variants of CaMKII␦ (␦ B and ␦ C ) characterized by the presence of a nuclear localization sequence in the variable domain (1,35,36). The NLS drives ␦ B homomultimers or ␦ B -enriched heteromultimers to the nucleus, whereas CaMKII␦ C subunit-rich multimeric enzyme would remain cytoplasmic.…”

Section: Discussionmentioning

confidence: 99%

CaMKIIδ Isoforms Differentially Affect Calcium Handling but Similarly Regulate HDAC/MEF2 Transcriptional Responses

Zhang

Kohlhaas

Backs

et al. 2007

Journal of Biological Chemistry

188

168

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The ␦ B and ␦ C 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 CaMKII␦ C isoform regulates cytosolic Ca 2؉ 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) Ca 2؉ spark frequency and decreased SR Ca 2؉ 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 Ca 2؉ handling, suggesting distinct roles for CaMKII␦ isoform activation in the pathogenesis of cardiac hypertrophy versus heart failure.is the predominant isoform of CaMKII in the heart. Splice variants differing in the presence of a nuclear localization sequence (NLS) show distinct subcellular targeting to either cytoplasmic or nuclear compartments (1-3). The CaMKII␦ B isoform contains an 11 amino acid NLS that is absent from ␦ C . Thus CaMKII heteromers comprised predominantly of ␦ B subunits localize to the nucleus while those with predominantly ␦ C localize to the cytoplasm (1-3). We recently demonstrated that both ␦ B and ␦ C CaMKII are activated in response to pressure overload induced by thoracic aortic banding but that expression of these isoforms is differentially regulated (4). The possibility that there are discrete roles for these two isoforms in regulating Ca 2ϩ homeostasis and gene transcription has not yet been explored.CaMKII has long been implicated as a regulator of Ca 2ϩ homeostasis and excitation-contraction (E-C) coupling in ventricular myocytes. This enzyme has been shown to phosphorylate proteins involved in sarcoplasmic reticulum (SR) Ca 2ϩ handling including the cardiac ryanodine receptors (RyR2) and phospholamban (PLB) (4 -10). Phosphorylation of the RyR2 appears to alter its channel open probability (9 -11) while phosphorylation of PLB by CaMKII can regulate SR Ca 2ϩ uptake (10, 12). Altered intracellular Ca 2ϩ handling plays an important role in the pathogenesis of heart failure with changes in Ca 2ϩ cycling pr...

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The cardiac sarcoplasmic reticulum phospholamban kinase is a distinct δ‐CaM kinase isozyme

Cited by 55 publications

References 35 publications

Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice

Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice

Identification and Expression of δ-Isoforms of the Multifunctional Ca ²⁺ /Calmodulin-Dependent Protein Kinase in Failing and Nonfailing Human Myocardium

CaMKIIδ Isoforms Differentially Affect Calcium Handling but Similarly Regulate HDAC/MEF2 Transcriptional Responses

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The cardiac sarcoplasmic reticulum phospholamban kinase is a distinct δ‐CaM kinase isozyme

Cited by 55 publications

References 35 publications

Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice

Requirement for Ca2+/calmodulin–dependent kinase II in the transition from pressure overload–induced cardiac hypertrophy to heart failure in mice

Identification and Expression of δ-Isoforms of the Multifunctional Ca 2+ /Calmodulin-Dependent Protein Kinase in Failing and Nonfailing Human Myocardium

CaMKIIδ Isoforms Differentially Affect Calcium Handling but Similarly Regulate HDAC/MEF2 Transcriptional Responses

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Identification and Expression of δ-Isoforms of the Multifunctional Ca ²⁺ /Calmodulin-Dependent Protein Kinase in Failing and Nonfailing Human Myocardium