Regulation of CaMKII by α4/PP2Ac contributes to learning and memory
Regulation of CaMKII by α4/PP2Ac contributes to learning and memory
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DOI：
10.1016/j.brainres.2006.01.101
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发表时间：
2006-04
期刊：
影响因子：
2.9
通讯作者：
Takeshi Yamashita;S. Inui;K. Maeda;D. Hua;K. Takagi;K. Fukunaga;N. Sakaguchi
中科院分区：
文献类型：
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作者：
Takeshi Yamashita;S. Inui;K. Maeda;D. Hua;K. Takagi;K. Fukunaga;N. Sakaguchi
钙依赖的CaMKIIα的自磷酸化激活在学习记忆中起着至关重要的作用。已证实通过蛋白磷酸酶1(PP1)去磷酸化来调节CaMKIIα。我们探讨了大脑中丰富的蛋白磷酸酶2A(PP2A)是否参与了CaMKIIα的调节。CaMKIIα与PP2A催化亚单位(PP2Ac)和PP2Ac的调节因子α4相关。为了探讨α4在中枢神经系统中是否起重要作用，我们建立了神经元特异性Cre转基因小鼠和神经元特异性α4缺陷小鼠(N-α4 KO小鼠)。这只N-α4KO小鼠在水迷宫和穿梭箱回避试验中表现出学习和记忆障碍。海马区CaMKIIα活性也升高。α-4在神经细胞中的过表达表明，α的活性受α-4的调节。α-4和α定位于胞浆，而不是突触后密度，提示α-4/PP2Ac对CaMK-II DNA的去磷酸化发生在胞浆。这些结果提示，α-4和PP2A可能在α调节中发挥重要作用，从而也影响学习。
Ca2+-dependent CaMKIIα activation with autophosphorylation plays an essential role in learning and memory. The regulation of CaMKIIα by dephosphorylation by protein phosphatase 1 (PP1) has been demonstrated. We addressed whether the protein phosphatase 2A (PP2A) that is abundant in the brain could be involved in the regulation of CaMKIIα. CaMKIIα was associated with the catalytic subunit of PP2A (PP2Ac) and α4, a regulator of PP2A. To investigate whether α4 plays an important role in the CNS, we established a neuron specific Cre transgenic mouse and a neuron specific α4 deficient mouse (N-α4 KO mouse). This N-α4 KO mouse showed impaired learning and memory in a water maze and also shuttle-box avoidance test. The activity of CaMKIIα also increased in hippocampus. An overexpression of α4 in the neuronal cell line demonstrated the activity of CaMKIIα to be regulated by α4. α4 and PP2Ac were localized in the cytoplasm but not in the postsynaptic density (PSD), thus suggesting that the dephosphorylation of CaMKIIα by α4/PP2Ac occurred in the cytoplasm. These results suggest that α4 and PP2A may thus play an important role in CaMKIIα regulation and thereby also influence learning.