Lead-Induced ERK Activation Is Mediated by GluR2 Non-containing AMPA Receptor in Cortical Neurons
Lead-Induced ERK Activation Is Mediated by GluR2 Non-containing AMPA Receptor in Cortical Neurons
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DOI：
10.1248/bpb.b16-00784
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发表时间：
2017-03-01
影响因子：
2
通讯作者：
Ohta, Shigeru
中科院分区：
文献类型：
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作者：
Ishida, Keishi;Kotake, Yaichiro;Ohta, Shigeru
铅是一种持久性环境污染物，暴露于高水平的环境中会引起各种有害毒性，特别是对中枢神经系统（CNS）。α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体缺乏谷氨酸受体2（GluR 2）亚基，是Ca 2+可渗透的，这增加了神经元对兴奋性毒性的脆弱性。我们以前曾报道，长期暴露于醋酸铅的大鼠皮层神经元诱导GluR 2的表达减少。然而，目前尚不清楚铅诱导的GluR 2降低是否涉及神经毒性。因此，我们研究了不含GluR 2的AMPA受体对铅诱导的神经毒性事件的贡献。虽然铅暴露降低了AMPA受体4个亚基（GluR 1、GluR 2、GluR 3和GluR 4）的表达，但其中GluR 2的表达降低最为显著。3种谷氨酸受体拮抗剂，6-氰基-7-硝基喹喔啉-2，3-二酮（CNQX，一种非选择性AMPA受体阻断剂），MK-801（N-甲基-N-天冬氨酸（NMDA）受体阻断剂）和1-萘基乙酰精胺（NAS，一种特异性Ca 2+渗透性AMPA受体阻断剂）挽救了铅诱导的神经元细胞死亡。铅暴露激活细胞外信号调节蛋白激酶（ERK）1/2，CNQX可显着改善该作用。此外，铅暴露激活了p38丝裂原活化蛋白激酶（MAPK p38）和蛋白激酶C（PKC），CNQX可部分改善这一点。我们的研究结果表明，Ca 2+渗透AMPA受体导致GluR 2减少可能参与铅诱导的神经毒性。
Lead is a persistent environmental pollutant and exposure to high environmental levels causes various deleterious toxicities, especially to the central nervous system (CNS). The alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor that is devoid of the glutamate receptor 2 (GluR2) subunit is Ca2+ -permeable, which increases the neuronal vulnerability to excitotoxicity. We have previously reported that long-term exposure of rat cortical neurons to lead acetate induces decrease of GluR2 expression. However, it is not clarified whether lead-induced GluR2 decrease is involved in neurotoxicity. Therefore, we investigated the contribution of GluR2 non-containing AMPA receptor to lead-induced neurotoxic events. Although the expression of four AMPA receptor subunits (GluR1, GluR2, GluR3, and GluR4) was decreased by lead exposure, the decrease in GluR2 expression was remarkable among four subunits. Lead-induced neuronal cell death was rescued by three glutamate receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, a non-selective AMPA receptor blocker), MK -801 (N-methyl-n-aspartate (NMDA) receptor blocker), and 1-naphthyl acetyl spermine (NAS, a specific Ca2+ -permeable AMPA receptor blocker). Lead exposure activated extracellular signal -regulated protein kinase (ERK) 1/2, which was significantly ameliorated by CNQX. In addition, lead exposure activated p38 mitogen-activated protein kinase (MAPK p38), and protein kinase C (PKC), which was partially ameliorated by CNQX. Our findings indicate that Ca2+ -permeable AMPA receptors resulting from GluR2 decrease may be involved in lead-induced neurotoxicity.