The calmodulin multigene family as a unique case of genetic redundancy: multiple levels of regulation to provide spatial and temporal control of calmodulin pools?

Calmodulin (CaM) is a ubiquitous, highly conserved calcium sensor protein i nvolved in the regulation of a wide variety of cellular events. In vertebra tes, an identical CaM protein is encoded by a family of non-allelic genes, raising questions concerning the evolutionary pressure responsible for the maintenance of this apparently redundant family, Here we review the evidenc e that the control of the spatial and temporal availability of CaM may requ ire multiple regulatory levels to ensure the proper localization, maintenan ce and size of intracellular CaM pools. Differential transcription of the C aM genes provides one level of regulation to meet tissue-specific, developm ental and cell-specific needs for altered CaM levels. Post-transcriptional regulation occurs at the level of mRNA stability, perhaps dependent on alte rnative polyadenylation and differences in the untranslated sequences of th e multiple gene transcripts. Recent evidence indicates that trafficking of specific CaM mRNAs may occur to specialized cellular locales such as the de ndrites of neurons. This could allow local CaM synthesis and thereby help g enerate local pools of CaM. Local CaM activity may be further regulated by post-translational mechanisms such as phosphorylation or storage of CaM in a 'masked' form. The spatial resolution of CaM activity is enhanced by the limited free diffusion of CaM combined with differential affinity for and a vailability of target proteins. Preserving multiple CaM genes with divergen t noncoding sequences may be necessary in complex organisms to ensure that the many CaM-dependent processes occur with the requisite spatial and tempo ral resolution. Transgenic mouse models and studies on mice carrying single and double gene 'knockouts' promise to shed further light on the role of s pecificity versus redundancy in the evolutionary maintenance of the vertebr ate CaM multigene family. (C) 2000 Harcourt Publishers Ltd.