Nuclear Ca2+ regulates cardiomyocyte function

In the heart, cytosolic Ca2+ signals are well-characterized events that participate in the activation of cell contraction. In contrast, nuclear Ca2+ contribution to cardiomyocyte function remains elusive. Here, we examined functional consequences of buffering nuclear Ca2+ in neonatal cardiomyocytes. We report that cardiomyocytes contain a nucleoplasmic reticulum, which expresses both ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor (InsP3R), providing a possible way for active regulation of nuclear Ca2+. Adenovirus constructs encoding the Ca2+ buffer protein parvalbumin were targeted to the nucleus with a nuclear localization signal (Ad-PV-NLS) or to the cytoplasm with a nuclear exclusion signal (Ad-PV-NES). A decrease in the amplitude of global Ca2+ transients and RyR-II expression, as well as an increase in cell beating rate were observed in Ad-PV-NES and Ad-PV-NLS cells. When nuclear Ca2+ buffering was imposed nuclear enlargement, increased calcineurin expression, NFAT translocation to the nucleus and subcellular redistribution of atrial natriuretic peptide were observed. Furthermore, prolongation of action potential duration occurred in adult ventricular myocytes. These results suggest that nuclear Ca2+ levels underlie the regulation of specific protein targets and thereby modulate cardiomyocyte function. The local nuclear Ca2+ signaling and the structures that control it constitute a novel regulatory motif in the heart.