Nuclear calcineurin is a sensor for detecting Ca release from the nuclear envelope via IPR.

In continuously beating cells like cardiac myocytes, there are rapid alterations of cytosolic Ca levels. We therefore hypothesize that decoding Ca signals for hypertrophic signaling requires intracellular Ca microdomains that are partly independent from cytosolic Ca. Furthermore, there is a need for a Ca sensor within these microdomains that translates Ca signals into hypertrophic signaling. Recent evidence suggested that the nucleus of cardiac myocytes might be a Ca microdomain and that calcineurin, once translocated into the nucleus, could act as a nuclear Ca sensor. We demonstrate that nuclear calcineurin was able to act as a nuclear Ca sensor detecting local Ca release from the nuclear envelope via IPR. Nuclear calcineurin mutants defective for Ca binding failed to activate NFAT-dependent transcription. Under hypertrophic conditions Ca 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. Measurements of nuclear and cytosolic Ca transients in IP sponge mice showed no increase of Ca 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 IPR2 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 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 sensor to promote NFAT activity. • Nuclear Ca in cardiac myocytes increases via IPR2 upon Ang II stimulation. • IPR2 expression is directly dependent on calcineurin/NFAT.