Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei, 230601, China.
Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, 30310, USA.
Mol Neurobiol. 2019 May;56(5):3326-3340. doi: 10.1007/s12035-018-1289-0. Epub 2018 Aug 17.
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 3 h could reduce ASIC1a protein expression, ASIC currents, and acid-induced [Ca] 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.
组织酸中毒是脑缺血的一个常见特征，会导致神经元损伤。酸感应离子通道 1a（ASIC1a）的激活在酸中毒介导的神经毒性中发挥重要作用。急性乙醇给药已被证明在缺血性中风期间提供神经保护作用，但确切的机制仍有待确定。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。我们表明，急性处理神经元细胞超过 3 小时的乙醇处理可降低 ASIC1a 蛋白表达、ASIC 电流和酸诱导的 [Ca]升高。我们进一步证明，乙醇诱导的 ASIC1a 表达减少是通过自噬溶酶体途径（ALP）依赖性蛋白降解介导的。最后，我们表明乙醇可保护神经元细胞免受酸中毒诱导的细胞毒性，自噬激活剂雷帕霉素模拟了这种作用，而自噬抑制剂 CQ 则消除了这种作用。总之，这些结果表明，适度的急性乙醇暴露可以促进自噬溶酶体途径依赖性 ASIC1a 蛋白降解，并防止酸中毒诱导的神经毒性。
