University of Oulu

Karppinen, S., Hänninen, S. L., Rapila, R., Tavi, P.. Sarcoplasmic reticulum Ca2+-induced Ca2+ release regulates class IIa HDAC localization in mouse embryonic cardiomyocytes. Physiol Rep, 6 ( 2), 2018, e13522,

Sarcoplasmic reticulum Ca²⁺-induced Ca²⁺ release regulates class IIa HDAC localization in mouse embryonic cardiomyocytes

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Author: Karppinen, Sari1; Hänninen, Sandra L.2; Rapila, Risto1;
Organizations: 1University of Eastern Finland Department of Biotechnology and Molecular Medicine Kuopio Finland
2Institute of Biomedicine, Department of Physiology and Biocenter Oulu, University of Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.6 MB)
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Language: English
Published: John Wiley & Sons, 2018
Publish Date: 2018-03-15


In embryonic cardiomyocytes, sarcoplasmic reticulum (SR)-derived Ca²⁺ release is required to induce Ca²⁺ oscillations for contraction and to control cardiac development through Ca²⁺-activated pathways. Here, our aim was to study how SR Ca²⁺ release regulates cytosolic and nuclear Ca²⁺ distribution and the subsequent effects on the Ca²⁺-dependent localization of class IIa histone deacetylases (HDAC) and cardiac-specific gene expression in embryonic cardiomyocytes. Confocal microscopy was used to study changes in Ca²⁺-distribution and localization of immunolabeled HDAC4 and HDAC5 upon changes in SR Ca²⁺ 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 Ca²⁺ release caused a significant decrease in intranuclear Ca²⁺ 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 Ca²⁺ release inhibition. Electrical stimulation of sarcolemmal Ca²⁺ influx was not sufficient to rescue either the HDAC localization or the gene expression changes. SR Ca²⁺ release controls subcellular Ca²⁺ distribution and regulates localization of HDAC4 and HDAC5 in embryonic cardiomyocytes. Changes in SR Ca²⁺ release also caused changes in expression of the developmental phase-specific genes, which may be due to the changes in HDAC-localization.

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Series: Physiological reports
ISSN: 2051-817X
ISSN-E: 2051-817X
ISSN-L: 2051-817X
Volume: 6
Issue: 2
Article number: e13522
DOI: 10.14814/phy2.13522
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
1184 Genetics, developmental biology, physiology
Funding: Funded by Sigrid Juselius Foundation, Finnish Foundation for Cardiac Research and Academy of Finland.
Copyright information: © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.