Sarcoplasmic reticulum Ca(2+)‐induced Ca(2+) release regulates class IIa HDAC localization in mouse embryonic cardiomyocytes

In embryonic cardiomyocytes, sarcoplasmic reticulum (SR)‐derived Ca(2+) release is required to induce Ca(2+) oscillations for contraction and to control cardiac development through Ca(2+)‐activated pathways. Here, our aim was to study how SR Ca(2+) release regulates cytosolic and nuclear Ca(2+) distribution and the subsequent effects on the Ca(2+)‐dependent localization of class IIa histone deacetylases (HDAC) and cardiac‐specific gene expression in embryonic cardiomyocytes. Confocal microscopy was used to study changes in Ca(2+)‐distribution and localization of immunolabeled HDAC4 and HDAC5 upon changes in SR Ca(2+) release in mouse embryonic cardiomyocytes. Dynamics of translocation were also observed with a confocal microscope, using HDAC5‐green fluorescent protein transfected myocytes. Expression of class IIa HDACs in differentiating myocytes and changes in cardiac‐specific gene expression were studied using real‐time quantitative PCR. Inhibition of SR Ca(2+) release caused a significant decrease in intranuclear Ca(2+) concentration, a rapid nuclear import of HDAC5 and subnuclear redistribution of HDAC4. Endogenous localization of HDAC5 and HDAC4 was mostly cytosolic and at the nuclear periphery, respectively. Downregulated expression of cardiac‐specific genes was also observed upon SR Ca(2+) release inhibition. Electrical stimulation of sarcolemmal Ca(2+) influx was not sufficient to rescue either the HDAC localization or the gene expression changes. SR Ca(2+) release controls subcellular Ca(2+) distribution and regulates localization of HDAC4 and HDAC5 in embryonic cardiomyocytes. Changes in SR Ca(2+) release also caused changes in expression of the developmental phase‐specific genes, which may be due to the changes in HDAC‐localization.