Proteasome inhibitor lactacystin disturbs the intracellular calcium homeostasis of dopamine neurons in ventral mesencephalic cultures
Proteasome inhibitor lactacystin disturbs the intracellular calcium homeostasis of dopamine neurons in ventral mesencephalic cultures
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DOI：
10.1016/j.neuint.2007.04.014
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发表时间：
2007-06-01
影响因子：
4.2
通讯作者：
Le, Weidong
中科院分区：
文献类型：
--
作者：
Li, Xuping;Yang, Dehua;Le, Weidong
泛素蛋白酶体系统（UPS）损伤与帕金森病的病理学有关，但UPS损伤诱导多巴胺（DA）神经元变性的机制尚不清楚。为探讨UPS损伤引起的DA神经元损伤是否与钙稳态紊乱有关，我们用蛋白酶体抑制剂lactacystin处理原代培养的中脑腹侧（VM），观察其对钙稳态相关基因Homer 1 a表达、细胞内游离钙（[Ca ~（2+）]（i））水平以及DA神经元存活的影响。我们还研究了L型电压依赖性钙通道（L-VDCC）在这些事件中的可能作用。我们发现，lactacystin暴露诱导Homer la表达，降低VM培养物中的[Ca 2 +]（i）水平，减少去极化诱导的钙内流和DA释放，并引起显著的DA神经元损失。氯化钾或其激动剂激活L-VDCC可减轻lactacystin对DA神经元[Ca ~（2+）]（i）水平的影响，促进DA神经元存活，而L-VDCC拮抗剂可阻断去极化介导的神经保护作用，高浓度L-VDCC拮抗剂可加重lactacystin诱导的DA神经元损伤。这些结果表明，钙稳态紊乱可能是导致DA神经元损伤的蛋白酶体抑制条件下的一种新的病理机制。(C)2007爱思唯尔有限公司保留所有权利。
Ubiquitin proteasome system (UPS) impairment has been implicated in the pathology of Parkinson's disease, but the mechanisms underlying the UPS impairment-induced dopamine (DA) neuron degeneration remain obscure. To test whether calcium homeostasis disturbance is involved in the DA neuronal injury resulting from UPS impairment, we treated the primary ventral mesencephalic (VM) cultures with the proteasome inhibitor lactacystin, and observed its effects on the expression of the gene Homer 1 a that is related to calcium homeostasis, and the intracellular free calcium ([Ca2+](i)) levels as well as the DA neuron survival. We also investigated a possible role of the L-type voltage dependent calcium channels (L-VDCC) in these events. We found that the lactacystin exposure induced the Homer la expression, lowered the [Ca2+](i) levels, reduced the depolarization-induced calcium entry and DA release in the VM cultures, and caused a significant DA neuron loss. Activation of L-VDCC by potassium chloride or its agonists alleviated the effects of lactacystin on the [Ca2+](i) levels and promoted DA neuron survival, whereas L-VDCC antagonists blocked the depolarization-mediated neuroprotective effect, and at high concentrations the L-VDCC antagonists aggravated the lactacystin-induced DA neuronal injury. These results indicate that calcium homeostasis disturbance may be a novel pathological mechanism leading to DA neuronal injury under conditions of proteasome inhibition. (C) 2007 Elsevier Ltd. All rights reserved.