Does Contractile Ca 2+ Control Calcineurin-NFAT Signaling and Pathological Hypertrophy in Cardiac Myocytes?

In noncontractile cells, a sustained increase in total cytoplasmic Ca(2+) concentration is typically needed to activate the intracellular protein phosphatase calcineurin, leading to dephosphorylation of the transcription factor nuclear factor of activated T cells (NFAT), its nuclear translocation, and induction of gene expression. It remains a mystery exactly how Ca(2+)-dependent signaling pathways, such as that mediated by calcineurin-NFAT, are regulated in contracting cardiac myocytes given the highly specialized manner in which Ca(2+) concentration rhythmically cycles in excitation-contraction coupling. Here, we critically review evidence that supports the hypothesis that calcineurin-NFAT signaling is regulated by contractile Ca(2+) transients in cardiac myocytes.