Negative regulation of multifunctional Ca2+/calmodulin-dependent protein kinases: physiological and pharmacological significance of protein phosphatases

Ishida Atsuhiko

Sueyoshi Noriyuki

Shigeri Yasushi

Kameshita Isamu

British Journal of Pharmacology

Multifunctional Ca2+/calmodulin-dependent protein kinases (CaMKs) play pivotal roles in intracellular Ca2+ signaling pathways. There is growing evidence that CaMKs are involved in the pathogenic mechanisms underlying various human diseases. In this review, we begin by briefly summarizing our knowledge of the involvement of CaMKs in the pathogenesis of various diseases suggested to be caused by the dysfunction/dysregulation or aberrant expression of CaMKs. It is widely known that the activities of CaMKs are strictly regulated by protein phosphorylation /dephosphorylation of specific phosphorylation sites. Since phosphorylation status is balanced by protein kinases and protein phosphatases, the mechanism of dephosphorylation/deactivation of CaMKs, corresponding to their “switching off", is extremely important, as is the mechanism of phosphorylation/activation corresponding to their “switching on". Therefore, we focus on the regulation of multifunctional CaMKs by protein phosphatases. We summarize the current understanding of negative regulation of CaMKs by protein phosphatases. We also discuss the biochemical properties and physiological significance of a protein phosphatase that we designated as Ca2+ /calmodulin-dependent protein kinase phosphatase (CaMKP), and those of its homologue CaMKP-N. Pharmacological applications of CaMKP inhibitors are also discussed. These compounds may be useful not only for exploring the physiological functions of CaMKP/CaMKP-N, but also as novel chemotherapies for various diseases.

Ca2+/calmodulin-dependent protein kinase

protein phosphatase

phosphorylation

dephosphorylation

deactivation

disease

pathogenesis

inhibitor

chemical screening

Medical sciences [ 490 ]

eng

Nature Publishing Group

Copyright (c) 2008 Nature Publishing Group

[ISSN] 0007-1188

[DOI] 10.1038/bjp.2008.127

[NCID] AA00574810

[PMID] 18454172

[DOI] http://dx.doi.org/10.1038/bjp.2008.127 isVersionOf