title: 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 Ca(2+) 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.
authors.affiliation: From the Department of Cell & Molecular Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153.
authors.forename: Natesan
authors.initials: N
authors.lastname: Sankar
authors.forename: Pieter P
authors.initials: PP
authors.lastname: deTombe
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Mignery
mesh_terms: D000328:Adult; D000818:Animals; D001896:Boron Compounds / Q000494:pharmacology; D019703:Calcineurin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D047028:Macrocyclic Compounds / Q000494:pharmacology; D008297:Male; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010080:Oxazoles / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C538758:2-aminoethyl diphenylborinate; D001896:Boron Compounds; C506927:ITPR2 protein, human; C506928:ITPR2 protein, rat; D053496:Inositol 1,4,5-Trisphosphate Receptors; D047028:Macrocyclic Compounds; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; C494005:Nfatc1 protein, mouse; D010080:Oxazoles; C511704:xestospongin C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin
keywords: Calcineurin; Calcium Signaling; Cardiac Hypertrophy; Gene Transcription; Inositol 1,4,5-Trisphosphate