Nuclear calcineurin is a sensor for detecting Ca 2+ release from the nuclear envelope via IP 3 R

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. • 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.