Activation of AMP-activated protein kinase by tributyltin induces neuronal cell death
Activation of AMP-activated protein kinase by tributyltin induces neuronal cell death
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DOI：
10.1016/j.taap.2008.03.021
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发表时间：
2008-08-01
影响因子：
3.8
通讯作者：
Ohta, Shigeru
中科院分区：
文献类型：
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作者：
Nakatsu, Yusuke;Kotake, Yaichiro;Ohta, Shigeru
腺苷酸活化蛋白激酶（AMPK）是代谢物敏感蛋白激酶家族的一员，在能量缺乏时被激活，并在神经元中大量表达。环境污染物三丁基氯化锡（TBT）是一种神经毒素，据报道会降低某些类型细胞的细胞ATP。因此，我们研究了TBT是否激活AMPK，以及它的激活是否有助于神经元细胞死亡，使用皮层神经元的原代培养。暴露于500 nM TBT后0.5 h，细胞ATP水平降低，且降低具有时间依赖性。结果表明，在我们的培养系统中，大多数神经元表达AMPK，TBT诱导AMPK磷酸化。AMPK抑制剂化合物C降低了TBT的神经毒性，表明AMPK参与了TBT诱导的细胞死亡。接下来，研究AMPK活化的下游靶标。一氧化氮合酶，p38磷酸化和Akt去磷酸化的TBT诱导的AMPK激活的下游，因为这些因素不受化合物C，但谷氨酸释放被认为是由AMPK控制。我们的研究结果表明，AMPK激活TBT通过介导谷氨酸释放引起神经元死亡。(C)2008年爱思唯尔公司All rights reserved.
AMP-activated protein kinase (AMPK), a member of the metabolite-sensing protein kinase family, is activated by energy deficiency and is abundantly expressed in neurons. The environmental pollutant, tributyltin chloride (TBT), is a neurotoxin, and has been reported to decrease cellular ATP in some types of cells. Therefore, we investigated whether TBT activates AMPK, and whether its activation contributes to neuronal cell death, using primary cultures of cortical neurons. Cellular ATP levels were decreased 0.5 h after exposure to 500 nM TBT, and the reduction was time-dependent. It was confirmed that most neurons in our culture system express AMPK, and that TBT induced phosphorylation of AMPK. Compound C, an AMPK inhibitor, reduced the neurotoxicity of TBT, suggesting that AMPK is involved in TBT-induced cell death. Next, the downstream target of AMPK activation was investigated. Nitric oxide synthase, p38 phosphorylation and Akt dephosphorylation were not downstream of TBT-induced AMPK activation because these factors were not affected by compound C, but glutamate release was suggested to be controlled by AMPK. Our results suggest that activation of AMPK by TBT causes neuronal death through mediating glutamate release. (C) 2008 Elsevier Inc. All rights reserved.