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

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.

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Funding

CHFC “heart failure” projects B2, C2 (BMBF), VIP0014 (BMBF), and DFG Ri1085/4-1 and Gesundheitscampus Brandenburg to O.R.

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Correspondence to Oliver Ritter.

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The authors have no potential conflict of interest.

Research involving human participants and/or animals

No human participants were involved in the presented studies. All animal studies were performed in accordance with national guidelines for the care and use of animals and have been approved by the local ethics committee and the local government.

Electronic supplementary material

“Ang II” representative movie of a fluo-4 loaded isolated adult ventricular mouse cardiomyocyte. Cells were stimulated at 1 Hz. Ang II stimulation led to a marked increase in nuclear fluo-4 fluorescence that was most prominent during diastole. (WMV 591 kb)

“No Ang II” displays the cell from supplemental movie 1 before addition of Ang II. (WMV 231 kb)

Supplemental Movie 1

“Ang II” representative movie of a fluo-4 loaded isolated adult ventricular mouse cardiomyocyte. Cells were stimulated at 1 Hz. Ang II stimulation led to a marked increase in nuclear fluo-4 fluorescence that was most prominent during diastole. (WMV 591 kb)

Supplemental Movie 2

“No Ang II” displays the cell from supplemental movie 1 before addition of Ang II. (WMV 231 kb)

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Olivares-Florez, S., Czolbe, M., Riediger, F. et al. Nuclear calcineurin is a sensor for detecting Ca2+ release from the nuclear envelope via IP3R. J Mol Med 96, 1239–1249 (2018). https://doi.org/10.1007/s00109-018-1701-2

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Keywords

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