Calcineurin-NFATc Regulates InsP3R2 Expression During Cardiac Remodeling [Gene Regulation]

January 10th, 2014 by Sankar, N., deTombe, P. P., Mignery, G. A.

In heart, the type-2 Inositol 1,4,5-triphosphate receptor (InsP3R2) is the predominant isoform expressed and is localized in the nuclear membrane of ventricular myocytes. InsP3R2 mediated Ca2+ release regulates hypertrophy specific gene expression by modulating CaMKII╬┤, HDAC and calcineurin-NFATc signaling pathways. InsP3R2 protein is a hypertrophy specific marker and is over-expressed in heart-failure animal models and in humans. However, the regulation of InsP3R2 mRNA and protein expression during cardiac hypertrophy and heart-failure is not known. Here we show the transcriptional regulation of the ITPR2 gene in adult cardiomyocytes. Our data demonstrates that, InsP3R2 mRNA and protein expression is activated by hypertrophic agonists and attenuated by the InsP3R inhibitors 2-APB and Xestospongin-C. The ITPR2 promoter is regulated by the calcineurin-NFATc signaling pathway. NFATc1 regulates ITPR2 gene expression by directly binding to the ITPR2 promoter. The calcineurin-NFATc mediated up-regulation of the ITPR2 promoter was attenuated by cyclosporine-A. InsP3R2 mRNA and protein expression were up-regulated in calcineurin-A transgenic mice and in human heart-failure. Collectively, our data suggests that ITPR2 and hypertrophy specific gene expression is regulated, in part, by a positive feed-back regulation between InsP3R2 and calcineurin-NFATc signaling pathways.