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.