Hormone-induced secretory and nuclear translocation of calmodulin: Oscillations of calmodulin concentration with the nucleus as an integrator

Many important enzyme activities are regulated by Ca(2+)-dependent interactions with calmodulin (CaM). Some of the most important targets for CaM action are in the nucleus, and Ca(2+)-dependent CaM translocation into this organelle has been reported. Hormone-evoked cytosolic Ca(2+) signals occur physiologically as oscillations, but, so far, oscillations in CaM concentration have not been described. We loaded fluorescent-labeled CaM into pancreatic acinar cells and monitored the fluorescence in various regions by confocal microscopy. Sustained high concentrations of the hormone cholecystokinin or the neurotransmitter acetylcholine evoked a transient movement of cytosolic CaM from the basal nonnuclear area into the secretory granule region and, thereafter, a more substantial and prolonged translocation of CaM into the nucleoplasm. About 50% of the CaM that bound Ca(2+) translocated. At a lower hormone concentration, evoking Ca(2+) oscillations, regular spikes of increased CaM concentration were seen in the secretory granule region with mirror image spikes of decreased CaM concentration in the basal nonnuclear region. The nucleus was able to integrate the Ca(2+) spike-evoked pulses of CaM translocation into a sustained elevation of the nucleoplasmic concentration of this protein.