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

• Published in: Journal of molecular medicine (Berlin, Germany) Germany), 2018-11, Vol.96 (11), p.1239-1249
• Main Authors: Olivares-Florez, Silvana, Czolbe, Martin, Riediger, Fabian, Seidlmayer, Lea, Williams, Tatjana, Nordbeck, Peter, Strasen, Jörn, Glocker, Cristina, Jänsch, Monique, Eder-Negrin, Petra, Arias-Loza, Paula, Mühlfelder, Melanie, Plačkić, Jelena, Heinze, Katrin G., Molkentin, Jeffery D., Engelhardt, Stefan, Kockskämper, Jens, Ritter, Oliver
• Format: Article
• Language: English
• Subjects: Angiotensin II; Biomedical and Life Sciences; Biomedicine; Calcineurin; Calcium (intracellular); Calcium ions; Calcium signalling; Cardiac muscle; Cardiomyocytes; Contraction; Cytosol; Decoding; Diastole; Eutrophication; Heart; Human Genetics; Inositol 1,4,5-trisphosphate receptors; Internal Medicine; Intracellular signalling; Mice; Molecular Medicine; Mutants; Myocytes; NF-AT protein; Original Article; Sensors; Transcription; Ventricle
• ISSN: 0946-2716; 1432-1440
• DOI: 10.1007/s00109-018-1701-2

In continuously beating cells like cardiac myocytes, there are rapid alterations of cytosolic Ca 2+ levels. We therefore hypothesize that decoding Ca 2+ signals for hypertrophic signaling requires intracellular Ca 2+ microdomains that are partly independent from cytosolic Ca 2+ . Furthermore, there is a need for a Ca 2+ sensor within these microdomains that translates Ca 2+ signals into hypertrophic signaling. Recent evidence suggested that the nucleus of cardiac myocytes might be a Ca 2+ microdomain and that calcineurin, once translocated into the nucleus, could act as a nuclear Ca 2+ sensor. We demonstrate that nuclear calcineurin was able to act as a nuclear Ca 2+ sensor detecting local Ca 2+ release from the nuclear envelope via IP 3 R. Nuclear calcineurin mutants defective for Ca 2+ binding failed to activate NFAT-dependent transcription. Under hypertrophic conditions Ca 2+ transients in the nuclear microdomain were significantly higher than in the cytosol providing a basis for sustained calcineurin/NFAT-mediated signaling uncoupled from cytosolic Ca 2+ . Measurements of nuclear and cytosolic Ca 2+ transients in IP 3 sponge mice showed no increase of Ca 2+ 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 IP 3 R2 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 Ca 2+ 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 Ca 2+ sensor to promote NFAT activity. • Nuclear Ca 2+ in cardiac myocytes increases via IP 3 R2 upon Ang II stimulation. • IP 3 R2 expression is directly dependent on calcineurin/NFAT.