The role of Ca2+/calmodulin-dependent protein kinases within the nucleus.

Stimulation of cells by Ca(2+)-linked signaling agents increases Ca2+ levels within both the cell cytosol and nucleus. The multifunctional Ca2+/calmodulin-dependent protein kinase (CaM kinase) family, consisting of CaM kinases I, II and IV, have all been detected within the nucleus and each may serve as a mediator of nuclear Ca2+ signals. Certain isoforms of the large multimeric CaM kinase II are targeted to the nucleus as a result of an alternatively spliced nuclear localization signal. By contrast, CaM kinases I and IV are monomeric and likely gain nuclear access by passive diffusion through nuclear pores. These kinases have activation properties which may allow them to discriminate between Ca2+ signals which differ in their spike frequency, amplitude and duration. In addition, these kinases have the ability to control gene expression through the phosphorylation of key regulatory sites on nuclear transcription factors. CaM kinases may thus serve to decode Ca2+ signals to the nucleus in order to produce a multitude of cellular responses including control of cell cycle, apoptosis and synaptic efficacy.