Ishida Atsuhiko, Shigeri Yasushi, Taniguchi Takanobu, Kameshita Isamu
Department of Biochemistry, Asahikawa Medical College, Asahikawa, 078-8510, Japan.
Pharmacol Ther. 2003 Dec;100(3):291-305. doi: 10.1016/j.pharmthera.2003.09.003.
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.
多功能钙/钙调蛋白依赖性蛋白激酶（CaMKs）在钙信号通路中发挥关键作用，如对学习、记忆和神经元细胞死亡等神经元功能的调节。这些激酶的活性受到蛋白质磷酸化/去磷酸化的严格调控。尽管通过磷酸化激活多功能CaMKs的机制（即“开启”机制）已得到广泛研究，但通过去磷酸化的负调控机制（即“关闭”机制）却尚未得到充分研究。在本综述中，我们重点关注了负责调控多功能CaMKs的蛋白磷酸酶。我们首先总结了目前对已知蛋白磷酸酶对CaMKs负调控的理解及其生理意义。然后我们讨论了用于检测参与CaMKs调控的蛋白磷酸酶的新开发方法。我们还总结了一种新型蛋白磷酸酶的生化特性，该酶是我们用新方法分离出来的，命名为CaMK磷酸酶（CaMKP）及其同源物。从通过关注参与其“关闭”机制的蛋白磷酸酶来阐明蛋白激酶活性调控的角度，讨论了其对包括记忆和神经元细胞死亡在内的神经元功能的药理学意义。
