Calcineurin signal transduction pathways in regulation of transcription factors involved in hypertrophic growth of cardiac myocytes. Sustained increases.

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Calcineurin signal transduction pathways in regulation of transcription factors involved in hypertrophic growth of cardiac myocytes. Sustained increases in intracellular Ca2+ concentrations, along with calmodulin (CaM), activate calcineurin, which in turn causes dephosphorylation of nuclear factor of activated T cells (NFAT), enabling NFAT to translocate to the nucleus where it interacts with GATA4 to regulate gene expression. Phosphorylation of NFAT is stimulated by glycogen synthase kinase 3β (GSK3β), whose activity is inhibited by activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway. Calcineurin also regulates CaM activation of CaM-dependent kinase (CaMK), which activates GATA transcription factor. CaMK also phosphorylates histone deacetylases (HDAC), leading to HDAC translocation from nucleus to cytoplasm. Otherwise, HDAC in the nucleus inhibits myocyte-enhancer factor 2 (MEF2) transcription activity. Cyclosporine A (CsA) and modulatory calcineurin-interacting protein (MCIP) inhibit calcineurin activation. Source: Toxic Responses of the Heart and Vascular System, Casarett and Doull's Toxicology: The Basic Science of Poisons, 8e Citation: Klaassen CD. Casarett and Doull's Toxicology: The Basic Science of Poisons, 8e; 2012 Available at: http://accesspharmacy.mhmedical.com/DownloadImage.aspx?image=/data/books/958/kla008_fig_18-06.png&sec=53490566&BookID=958&ChapterSecID=53483740&imagename= Accessed: December 23, 2017 Copyright © 2017 McGraw-Hill Education. All rights reserved