BDNF-mediated signal transduction is modulated by GSK3β and mood stabilizing agents
BDNF-mediated signal transduction is modulated by GSK3β and mood stabilizing agents
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DOI：
10.1046/j.1471-4159.2002.00939.x
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发表时间：
2002-07-01
影响因子：
4.7
通讯作者：
Li, XH
中科院分区：
文献类型：
--
作者：
Mai, L;Jope, RS;Li, XH
脑源性神经营养因子（BDNF）是脑内主要的神经营养因子，BDNF的异常调节可能参与心境障碍的病理生理。在本研究中，我们研究了糖原合成酶激酶3- β (gsk3 β)活性的改变或情绪稳定剂的治疗是否会调节分化的人神经母细胞瘤SH-SY5Y细胞中bdnf介导的信号转导途径。BDNF通过激活磷脂酰肌醇3-激酶(PI3K)/Akt信号通路增加叉头转录因子FKHRL1的磷酸化，通过激活细胞外信号调节激酶1/2 （ERK1/2）增加环AMP反应元件结合蛋白（CREB）的磷酸化。BDNF还增加gsk3 β的丝氨酸(9)磷酸化，从而抑制gsk3 β的活性。过表达gsk3 β不影响BDNF诱导的Akt、ERK1/2或FKHRL1的磷酸化，但可消除BDNF诱导的CREB磷酸化。在过表达gsk3beta的SH-SY5Y细胞中，bdnf诱导的CREB磷酸化的抑制作用被锂处理阻断。与锂相比，丙戊酸钠和拉莫三嗪不影响BDNF介导的信号传导，而卡马西平在缺乏或存在BDNF的情况下诱导ERK1/2和CREB的快速和延长的磷酸化。因此，增加的gsk3 β选择性地减弱bdnf诱导的CREB磷酸化，锂和卡马西平可以促进CREB的激活。
Brain-derived neurotrophic factor (BDNF) is a major neurotrophin in the brain and abnormal regulation of BDNF may contribute to the pathophysiology of mood disorders. In the present study, we examined if alterations in the activity of glycogen synthase kinase-3-beta (GSK3beta) or treatment with mood stabilizers modulated BDNF-mediated signal transduction pathways in differentiated human neuroblastoma SH-SY5Y cells. BDNF increased the phosphorylation of the forkhead transcription factor FKHRL1 through activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, and the phosphorylation of the cyclic AMP response element binding protein (CREB) through activation of extracellular signal-regulated kinase1/2 (ERK1/2). BDNF also increased serine(9)-phosphorylation of GSK3beta, which inhibits GSK3beta activity. Overexpression of GSK3beta did not affect BDNF-induced phosphorylation of Akt, ERK1/2, or FKHRL1, but abolished CREB phosphorylation induced by BDNF. This inhibition of BDNF-induced CREB phosphorylation in GSK3beta-overexpressing SH-SY5Y cells was blocked by treatment with lithium. In contrast to lithium, sodium valproate and lamotrigine did not affect BDNF-mediated signaling, whereas carbamazepine induced a rapid and prolonged phosphorylation of ERK1/2 and CREB in the absence or the presence of BDNF. Therefore, increased GSK3beta selectively attenuates BDNF-induced CREB phosphorylation, and lithium and carbamazepine can facilitate activation of CREB.