Format

Send to

Choose Destination
J Mol Med (Berl). 2018 Nov;96(11):1239-1249. doi: 10.1007/s00109-018-1701-2. Epub 2018 Oct 6.

Nuclear calcineurin is a sensor for detecting Ca2+ release from the nuclear envelope via IP3R.

Author information

1
Department of Internal Medicine I-Cardiology, University Hospital Würzburg, 97080, Würzburg, Germany.
2
Comprehensive Heart Failure Center, University Hospital Würzburg, 97080, Würzburg, Germany.
3
Department of Cardiology, Nephrology and Pulmonology, Brandenburg Medical School, University Hospital Brandenburg, 14770, Brandenburg/Havel, Germany.
4
Institute of Pharmacology and Clinical Pharmacy, Philips-University Marburg, 35033, Marburg, Germany.
5
Rudolf-Virchow-Center, Julius-Maximilians-University, 97080, Würzburg, Germany.
6
Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Howard Hughes Medical Institute, University of Cincinnati, Cincinnati, OH, 20815, USA.
7
Institute of Pharmacology and Toxicology, Technische Universität München, 80802, Munich, Germany.
8
DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, 80802, Munich, Germany.
9
Department of Internal Medicine I-Cardiology, University Hospital Würzburg, 97080, Würzburg, Germany. o.ritter@klinikum-brandenburg.de.
10
Comprehensive Heart Failure Center, University Hospital Würzburg, 97080, Würzburg, Germany. o.ritter@klinikum-brandenburg.de.
11
Department of Cardiology, Nephrology and Pulmonology, Brandenburg Medical School, University Hospital Brandenburg, 14770, Brandenburg/Havel, Germany. o.ritter@klinikum-brandenburg.de.

Abstract

In continuously beating cells like cardiac myocytes, there are rapid alterations of cytosolic Ca2+ levels. We therefore hypothesize that decoding Ca2+ signals for hypertrophic signaling requires intracellular Ca2+ microdomains that are partly independent from cytosolic Ca2+. Furthermore, there is a need for a Ca2+ sensor within these microdomains that translates Ca2+ signals into hypertrophic signaling. Recent evidence suggested that the nucleus of cardiac myocytes might be a Ca2+ microdomain and that calcineurin, once translocated into the nucleus, could act as a nuclear Ca2+ sensor. We demonstrate that nuclear calcineurin was able to act as a nuclear Ca2+ sensor detecting local Ca2+ release from the nuclear envelope via IP3R. Nuclear calcineurin mutants defective for Ca2+ binding failed to activate NFAT-dependent transcription. Under hypertrophic conditions Ca2+ transients in the nuclear microdomain were significantly higher than in the cytosol providing a basis for sustained calcineurin/NFAT-mediated signaling uncoupled from cytosolic Ca2+. Measurements of nuclear and cytosolic Ca2+ transients in IP3 sponge mice showed no increase of Ca2+ levels during diastole as we detected in wild-type mice. Nuclei, isolated from ventricular myocytes of mice after chronic Ang II treatment, showed an elevation of IP3R2 expression which was dependent on calcineurin/NFAT signaling and persisted for 3 weeks after removal of the Ang II stimulus. These data provide an explanation how Ca2+ and calcineurin might regulate transcription in cardiomyocytes in response to neurohumoral signals independently from their role in cardiac contraction control. KEY MESSAGES: • Calcineurin acts as an intranuclear Ca2+ sensor to promote NFAT activity. • Nuclear Ca2+ in cardiac myocytes increases via IP3R2 upon Ang II stimulation. • IP3R2 expression is directly dependent on calcineurin/NFAT.

KEYWORDS:

Calcineurin/NFAT signaling; Heart failure; IP3R2 receptor; Myocardial hypertrophy; Nuclear Ca2+

PMID:
30293136
DOI:
10.1007/s00109-018-1701-2

Supplemental Content

Full text links

Icon for Springer
Loading ...
Support Center