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

The δ_B and δ_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 CaMKIIδ_C isoform regulates cytosolic Ca²⁺ handling and the δ_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 CaMKIIδ_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 CaMKIIδ_B. In contrast, cardiac expression of either CaMKIIδ_B or δ_C induced transactivation of myocyte enhancer factor 2 (MEF2) gene expression and up-regulated hypertrophic marker genes. Studies using rat ventricular cardiomyocytes confirmed that CaMKIIδ_B and δ_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 CaMKIIδ_B or δ_C 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.