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

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.