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Impact of CaMKII Localization on Function

The delta isoform of Ca2+/Calmodulin dependent protein kinase II (CaMKII) is the predominant cardiac isoform and both nuclear targeted deltaB (dB) and cytoplasmic deltaC (dC) splice variants are present in the heart. We previously reported that transgenic (TG) expression of CaMKII dB induces cardiac hypertrophy while TG expression of CaMKII dC leads to dilated cardiomyopathy and heart failure. Based on immunostaining, we suggested that localization of the two isoforms was distinct and that nuclear CaMKII affects gene expression while cytosolic CaMKII primarily affects Ca2+ handling. Surprisingly, we found that hypertrophic gene expression in vivo and in vitro was affected by both CaMKII dB and dC. Subcellular fractionation of hearts isolated from CaMKII dB and dC TG mice showed that a fraction of the CaMKII dC transgene was present in the nucleus and a fraction of CaMKII dB appeared in the cytosol. When neonatal rat ventricular myocytes were infected with CaMKII dB or dC, similar observations were made. These findings suggest that overexpression of a particular isoform may affect its cellular localization by influencing the organization of the individual subunits within the CaMKII heteromultimer. We are currently investigating the subcellular localization of agonist‐activated CaMKII and examining apoptosis as an endpoint to determine whether isoform selectivity for this response depends on its localization.