The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth
The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth
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DOI：
10.1074/jbc.m104309200
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发表时间：
2001-08-24
影响因子：
4.8
通讯作者：
Chen, G
中科院分区：
文献类型：
--
作者：
Yuan, PX;Huang, LD;Chen, G
情绪稳定剂锂和丙戊酸（VPA）可提高培养细胞和大脑中与情绪调节有关的区域中AP-1转录因子的DNA结合活性和反激活活性，以及AP-1调控基因的表达。在本研究中，我们发现VPA激活了细胞外信号调节激酶（ERK）， ERK是一种已知的调节AP-1功能的激酶，并被神经营养素利用来介导其多种作用，包括神经元分化，神经元存活，长期神经可塑性，以及潜在的学习和记忆。vpa诱导的ERK活化被丝裂原活化蛋白激酶/ERK激酶抑制剂PD098059和显性阴性Ras和Raf突变体阻断，而不被显性阴性应激活化蛋白激酶/ERK激酶和丝裂原活化蛋白激酶激酶6突变体阻断。VPA还增加了ERK通路调控基因，包括生长锥相关蛋白43和Bcl-2的表达，促进神经突生长和细胞存活，增强去甲肾上腺素的摄取和释放。这些数据表明VPA是一种ERK通路激活剂并产生神经营养效应。
The mood-stabilizing agents lithium and valproic acid (VPA) increase DNA binding activity and transactivation activity of AP-1 transcription factors, as wen as the expression of genes regulated by AP-1, in cultured cells and brain regions involved in mood regulation. In the present study, we found that VPA activated extracellular signal-regulated kinase (ERK), a kinase known to regulate AP-1 function and utilized by neurotrophins to mediate their diverse effects, including neuronal differentiation, neuronal survival, long term neuroplasticity, and potentially learning and memory. VPA-induced activation of ERK was blocked by the mitogen-activated protein kinase/ERK kinase inhibitor PD098059 and dominant-negative Ras and Raf mutants but not by dominant-negative stress-activated protein kinase/ERK kinase and mitogen-activated protein kinase kinase 6 mutants. VPA also increased the expression of genes regulated by the ERK pathway, including growth cone-associated protein 43 and Bcl-2, promoted neurite growth and cell survival, and enhanced norepinephrine uptake and release. These data demonstrate that VPA is an ERK pathway activator and produces neurotrophic effects.