Calcineurin-NFATc Regulates Type 2 Inositol 1,4,5-Trisphosphate Receptor (InsP₃R2) Expression during Cardiac Remodeling*

Abstract

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 CaMKIIδ, histone deacetylase, and calcineurin-NFATc signaling pathways. InsP₃R2 protein is a hypertrophy specific marker and is overexpressed 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 InsP₃R inhibitors 2-aminoethoxyldiphenyl borate 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 was 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 feedback regulation between InsP₃R2 and calcineurin-NFATc signaling pathways.