Increased Expression of the Transient Receptor Potential Melastatin 7 Channel Is Critically Involved in Lipopolysaccharide-Induced Reactive Oxygen Species-Mediated Neuronal Death
Increased Expression of the Transient Receptor Potential Melastatin 7 Channel Is Critically Involved in Lipopolysaccharide-Induced Reactive Oxygen Species-Mediated Neuronal Death
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DOI：
10.1089/ars.2010.3825
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发表时间：
2011-11-01
影响因子：
6.6
通讯作者：
Simon, Felipe
中科院分区：
文献类型：
--
作者：
Nunez-Villena, Felipe;Becerra, Alvaro;Simon, Felipe
目的：为了探讨脂多糖(LPS)诱导神经细胞死亡的机制，我们检测了内毒素暴露对分化的PC12神经元和原代海马神经元的影响。结果：我们的数据表明，内毒素能够诱导PC12神经细胞死亡，而不需要神经胶质细胞的参与。神经细胞死亡是由细胞内活性氧簇(ROS)水平升高所介导的。考虑到特定离子通道在介导ROS有害效应中的普遍作用，我们评估了它们在这一过程中的贡献。暴露于内毒素的神经元表现出明显的细胞内钙超载，非选择性阳离子通道阻滞剂可抑制内毒素诱导的神经元死亡。特别是，我们观察到，内毒素和过氧化氢暴露都强烈地增加了瞬时受体蛋白Melastatin 7(TRPM7)的表达，这是一种直接与神经细胞死亡有关的离子通道。此外，二硫苏糖醇、地非利定和载脂蛋白均可减少内毒素诱导的TRPM7过度表达和内毒素诱导的神经元死亡。最后，使用小干扰RNA技术抑制TRPM7的表达保护了原代海马神经元，并分化了PC12神经元，使其免受内毒素的攻击。创新：这是第一个表明TRPM7是参与内毒素刺激后神经元死亡的关键蛋白的报告。结论：内毒素促进ROS依赖的TRPM7异常过度表达，在病理事件中发挥重要作用，从而导致神经元功能障碍和死亡。抗氧化剂。氧化还原信号。15,2425-2438。
Aims: To assess the mechanisms involved in lipopolysaccharide (LPS)-induced neuronal cell death, we examined the cellular consequences of LPS exposure in differentiated PC12 neurons and primary hippocampal neurons. Results: Our data show that LPS is able to induce PC12 neuronal cell death without the participation of glial cells. Neuronal cell death was mediated by an increase in cellular reactive oxygen species (ROS) levels. Considering the prevalent role of specific ion channels in mediating the deleterious effect of ROS, we assessed their contribution to this process. Neurons exposed to LPS showed a significant intracellular Ca2+ overload, and nonselective cationic channel blockers inhibited LPS-induced neuronal death. In particular, we observed that both LPS and hydrogen peroxide exposure strongly increased the expression of the transient receptor protein melastatin 7 (TRPM7), which is an ion channel directly implicated in neuronal cell death. Further, both LPS-induced TRPM7 overexpression and LPS-induced neuronal cell death were decreased with dithiothreitol, dipheniliodonium, and apocynin. Finally, knockdown of TRPM7 expression using small interference RNA technology protected primary hippocampal neurons and differentiated PC12 neurons from the LPS challenge. Innovation: This is the first report showing that TRPM7 is a key protein involved in neuronal death after LPS challenge. Conclusion: We conclude that LPS promotes an abnormal ROS-dependent TRPM7 overexpression, which plays a crucial role in pathologic events, thus leading to neuronal dysfunction and death. Antioxid. Redox Signal. 15, 2425-2438.