Kasahara J, Fukunaga K, Miyamoto E
Department of Pharmacology, Kumamoto University School of Medicine, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
J Biol Chem. 2001 Jun 29;276(26):24044-50. doi: 10.1074/jbc.M100247200. Epub 2001 Apr 16.
The importance of well characterized calcium/calmodulin-dependent protein kinase (CaMK) II in hippocampal long term potentiation (LTP) is widely well established; however, several CaMKs other than CaMKII are not yet clearly characterized and understood. Here we report the activation of CaMKIV, which is phosphorylated by CaMK kinase and localized predominantly in neuronal nuclei, and its functional role as a cyclic AMP-responsive element-binding protein (CREB) kinase in high frequency stimulation (HFS)-induced LTP in the rat hippocampal CA1 region. CaMKIV was transiently activated in neuronal nuclei after HFS, and the activation returned to the basal level within 30 min. Phosphorylation of CREB, which is a CaMKIV substrate, and expression of c-Fos protein, which is regulated by CREB, increased during LTP. This increase was inhibited mainly by CaMK inhibitors and also by an inhibitor for mitogen-activated protein kinase cascade, although to a lesser extent. Our results suggest that CaMKIV functions as a CREB kinase and controls CREB-regulated gene expression during HFS-induced LTP in the rat hippocampal CA1 region.
特性明确的钙/钙调蛋白依赖性蛋白激酶（CaMK）II在海马体长期增强（LTP）中的重要性已得到广泛充分的确立；然而，除CaMKII之外的几种CaMK尚未得到清晰的特性描述和理解。在此我们报告了CaMKIV的激活情况，它由CaMK激酶磷酸化，主要定位于神经元细胞核，并且在大鼠海马体CA1区高频刺激（HFS）诱导的LTP中作为一种环磷酸腺苷反应元件结合蛋白（CREB）激酶发挥功能作用。HFS后CaMKIV在神经元细胞核中被短暂激活，且激活在30分钟内恢复到基础水平。作为CaMKIV底物的CREB的磷酸化以及受CREB调控的c-Fos蛋白的表达在LTP期间增加。这种增加主要受到CaMK抑制剂的抑制，也受到丝裂原活化蛋白激酶级联反应抑制剂的抑制，不过程度较小。我们的结果表明，CaMKIV在大鼠海马体CA1区HFS诱导的LTP过程中作为一种CREB激酶发挥作用并控制CREB调控的基因表达。
