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

Olivares-Florez S, Czolbe M, Riediger F, Seidlmayer L, Williams T, Nordbeck P, Strasen J, Glocker C, Jaensch M, Eder-Negrin P, Arias-Loza P, Muehlfelder M, Plackic J, Heinze KG, Molkentin JD, Engelhardt S, Kockskaemper J, Ritter O (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Journal of Molecular Medicine Springer Verlag (Germany)

Book Volume: 96

Pages Range: 1239-1249

Journal Issue: 11

DOI: 10.1007/s00109-018-1701-2

Abstract

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.

Involved external institutions

Universitätsklinikum Würzburg

Germany (DE) Medizinische Hochschule Brandenburg "Theodor Fontane" / Brandenburg Medical School "Theodor Fontane"

Germany (DE) Philipps-Universität Marburg

Germany (DE) Julius-Maximilians-Universität Würzburg

Germany (DE) University of Cincinnati

United States (USA) (US) Technische Universität München (TUM)

Germany (DE)

How to cite

APA:

Olivares-Florez, S., Czolbe, M., Riediger, F., Seidlmayer, L., Williams, T., Nordbeck, P.,... Ritter, O. (2018). Nuclear calcineurin is a sensor for detecting Ca2+ release from the nuclear envelope via IP3R. Journal of Molecular Medicine, 96(11), 1239-1249. https://doi.org/10.1007/s00109-018-1701-2

MLA:

Olivares-Florez, Silvana, et al. "Nuclear calcineurin is a sensor for detecting Ca2+ release from the nuclear envelope via IP3R." Journal of Molecular Medicine 96.11 (2018): 1239-1249.

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