Inhibitors of the Ca2+/calmodulin-dependent protein kinase phosphatase family (CaMKP and CaMKP-N)
Inhibitors of the Ca2+/calmodulin-dependent protein kinase phosphatase family (CaMKP and CaMKP-N)
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DOI：
10.1016/j.bbrc.2007.09.022
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发表时间：
2007-11-23
影响因子：
3.1
通讯作者：
Ishida, Atsuhiko
中科院分区：
文献类型：
--
作者：
Sueyoshi, Noriyuki;Takao, Toshihiko;Ishida, Atsuhiko
钙/钙调素依赖的蛋白激酶磷酸酶(CaMKP)及其核异构体CaMKP-N是一种独特的Ser/Thr蛋白磷酸酶，它通过去磷酸化多功能的CaMKI、II和IV来负性调节钙/钙调素依赖的蛋白激酶(CaMK)级联反应。然而，缺乏这些磷酸酶的特异性抑制剂阻碍了对这些酶的体内研究。为了获得特异性的抑制剂，我们搜索了抑制化合物，发现埃文斯蓝和芝加哥天空蓝6B是CaMKP的有效抑制剂。这些化合物也抑制CaMKP-N，但既不抑制PPM家族另一成员蛋白磷酸酶2C，也不抑制典型的PPP家族磷酸酶钙调神经磷酸酶。抑制作用所需的最小结构为1-氨基-8-萘酚-4-磺酸。当用这些化合物处理共转CaMKIV和CaMKP-N的Neuro2a细胞时，CaMKIV的去磷酸化被强烈地抑制，这表明这些化合物在体内和体外都可以作为CaMKP和CaMKP-N的有效抑制剂。(C)2007 Elsevier Inc.保留所有权利。
Ca2+/calmodulin-dependent protein kinase phosphatase (CaMKP) and its nuclear isoform CaMKP-N are unique Ser/Thr protein phosphatases that negatively regulate the Ca2+/calmodulin-dependent protein kinase (CaMK) cascade by dephosphorylating multifunctional CaMKI, II, and IV. However, the lack of specific inhibitors of these phosphatases has hampered studies on these enzymes in vivo. In an attempt to obtain specific inhibitors, we searched inhibitory compounds and found that Evans Blue and Chicago Sky Blue 6B served as effective inhibitors for CaMKP. These compounds also inhibited CaMKP-N, but inhibited neither protein phosphatase 2C, another member of PPM family phosphatase, nor calcineurin, a typical PPP family phosphatase. The minimum structure required for the inhibition was 1-amino-8-naphthol-4-sulfonic acid. When Neuro2a, cells cotransfected with CaMKIV and CaMKP-N were treated with these compounds, the dephosphorylation of CaMKIV was strongly suppressed, suggesting that these compounds could be used as potent inhibitors of CaMKP and CaMKP-N in vivo as well as in vitro. (C) 2007 Elsevier Inc. All rights reserved.