Multifunctional Ca(2+)/calmodulin-dependent protein kinases (CaMKs) play pivotal roles in Ca(2+) signaling pathways, such as the regulation of the neuronal functions of learning, memory, and neuronal cell death. The activities of the kinases are strictly regulated by protein phosphorylation/dephosphorylation. Although the activation mechanisms for multifunctional CaMKs through phosphorylation, which correspond to "switch on," have been extensively studied, the negative regulatory mechanisms through dephosphorylation, which correspond to "switch off," have not. In this review, we focused on the regulation of multifunctional CaMKs by the protein phosphatases responsible. We first summarized the current understanding of negative regulation of CaMKs by known protein phosphatases and their physiological significance. We then discussed newly developed methods for detection of protein phosphatases involved in the regulation of CaMKs. We also summarized the biochemical properties of a novel protein phosphatase, which we isolated with the new methods and designated as CaMK phosphatase (CaMKP), and its homologue. Pharmacological implications for neuronal functions including memory and neuronal cell death are discussed from the viewpoint that regulation of protein kinase activity can be elucidated by focusing on protein phosphatases involved in its "switch off" mechanism.
