Acute Ethanol Exposure Promotes Autophagy-Lysosome Pathway-Dependent ASIC1a Protein Degradation and Protects Against Acidosis-Induced Neurotoxicity
Acute Ethanol Exposure Promotes Autophagy-Lysosome Pathway-Dependent ASIC1a Protein Degradation and Protects Against Acidosis-Induced Neurotoxicity
复制标题
急性乙醇暴露促进自噬溶酶体途径依赖性 ASIC1a 蛋白降解并防止酸中毒引起的神经毒性。
DOI：
10.1007/s12035-018-1289-0
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发表时间：
2019-05-01
影响因子：
5.1
通讯作者：
Xiong, Zhi-Gang
中科院分区：
文献类型：
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作者：
Zhou, Ren-Peng;Leng, Tian-Dong;Xiong, Zhi-Gang
组织酸中毒是脑缺血引起神经元损伤的常见特征。酸敏感离子通道1a （ASIC1a）的激活在酸中毒介导的神经毒性中起重要作用。急性乙醇管理已被证明在缺血性中风期间提供神经保护作用，但精确的机制尚未确定。在这项研究中，我们研究了乙醇对ASIC1a通道活性/表达和酸中毒诱导的神经毒性的影响。我们发现，用乙醇急性处理神经元细胞超过3小时，可以降低ASIC1a蛋白表达、ASIC电流和酸诱导的[Ca2+](i)升高。我们进一步证明，乙醇诱导的ASIC1a表达减少是由自噬-溶酶体途径（ALP）依赖的蛋白质降解介导的。最后，我们发现乙醇可以保护神经元细胞免受酸中毒诱导的细胞毒性，这种作用可以被自噬激活剂雷帕霉素模拟，并被自噬抑制剂CQ消除。总之，这些结果表明，中度急性乙醇暴露可以促进自噬-溶酶体途径依赖的ASIC1a蛋白降解，并保护免受酸中毒诱导的神经毒性。
Tissue acidosis is a common feature of brain ischemia which causes neuronal injury. Activation of acid-sensing ion channel 1a (ASIC1a) plays an important role in acidosis-mediated neurotoxicity. Acute ethanol administration has been shown to provide neuroprotective effects during ischemic stroke, but the precise mechanisms have yet to be determined. In this study, we investigated the effect of ethanol on the activity/expression of ASIC1a channels and acidosis-induced neurotoxicity. We showed that acute treatment of neuronal cells with ethanol for more than 3h could reduce ASIC1a protein expression, ASIC currents, and acid-induced [Ca2+](i) elevation. We further demonstrated that ethanol-induced reduction of ASIC1a expression is mediated by autophagy-lysosome pathway (ALP)-dependent protein degradation. Finally, we showed that ethanol protected neuronal cells against acidosis-induced cytotoxicity, which effect was mimicked by autophagy activator rapamycin and abolished by autophagy inhibitor CQ. Together, these results indicate that moderate acute ethanol exposure can promote autophagy-lysosome pathway-dependent ASIC1a protein degradation and protect against acidosis-induced neurotoxicity.