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Cardiomyocyte Calcium and Calcium/Calmodulin-dependent Protein Kinase II: Friends or Foes?

Department of Pharmacology, University of California, San Diego, La Jolla, California 92093

Calcium (Ca²⁺) is a critical second messenger in cell signaling. Elevated intracellular Ca²⁺ can activate numerous Ca²⁺-regulated enzymes. These enzymes have different subcellular localizations and may respond to distinct modes of Ca²⁺ mobilization. In cardiac muscle, Ca²⁺ plays a central role in regulating contractility, gene expression, hypertrophy, and apoptosis. Many cellular responses to Ca²⁺ signals are mediated by Ca²⁺/calmodulin-dependent enzymes, among which is the Ca²⁺/calmodulin-dependent protein kinase II (CaMKII). Putative substrates for CaMKII include proteins involved in regulating Ca²⁺ storage and release, transcription factors, and ion channels. The major isoform of CaMKII in the heart is CaMKII. Two cardiac splice variants, CaMKII_B and _C, differ in whether they contain a nuclear localization sequence. Our laboratory has examined the hypothesis that the nuclear _B and the cytoplasmic _C isoforms respond to different Ca²⁺ stimuli and have distinct effects on hypertrophic cardiac growth and Ca²⁺ handling. We have shown that pressure overload-induced hypertrophy differentially affects the nuclear _B and the cytoplasmic _C isoforms of CaMKII. Additionally, using isolated myocytes and transgenic mouse models, we demonstrated that the nuclear CaMKII_B isoform plays a key role in cardiac gene expression associated with cardiac hypertrophy. The cytoplasmic CaMKII_C isoform phosphorylates substrates involved in Ca²⁺ handling. Dysregulation of intracellular Ca²⁺ and resulting changes in excitation-contraction coupling characterize heart failure and can be induced by in vivo overexpression of CaMKII_C and phosphorylation of its substrates. The differential location of CaMKII isoforms and their relative activation by physiological vs. pathological stimuli may provide a paradigm for exploring and elucidating how Ca²⁺/CaMKII pathways can serve as both friends and foes in the heart.

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