General Anesthetics Regulate Autophagy via Modulating the Inositol 1,4,5-Trisphosphate Receptor: Implications for Dual Effects of Cytoprotection and Cytotoxicity.
General Anesthetics Regulate Autophagy via Modulating the Inositol 1,4,5-Trisphosphate Receptor: Implications for Dual Effects of Cytoprotection and Cytotoxicity.
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DOI：
10.1038/s41598-017-11607-0
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发表时间：
2017-09-28
影响因子：
4.6
通讯作者：
Wei H
中科院分区：
文献类型：
--
作者：
Ren G;Zhou Y;Liang G;Yang B;Yang M;King A;Wei H
全身麻醉剂既具有神经保护作用，又具有神经毒性，但机制尚不清楚。全身麻醉剂可以通过激活 1 型肌醇三磷酸受体 (InsP3R-1) 对自噬的影响来控制细胞存活。仅具有或超过99%表达InsP3R-1的DT40或SH-SY5Y细胞用异氟烷或丙泊酚处理。通过 MTT 还原或 LDH 释放测定来测定细胞活力。通过测量 Caspase-3 或通过 TUNEL 测定来确定细胞凋亡。通过测量 LC3 II 和 P62 来确定自噬活性。我们使用 MitoTracker Green 和胞质 ATP 水平评估线粒体完整性。 Fura2-AM 用于测量胞质钙 ([Ca2+]c) 的浓度。异丙酚显着增加 InsP3R-1 细胞中的峰值和积分钙反应 (P < 0.001)，但在 InsP3R 三重敲除细胞中则不然。丙泊酚和异氟烷均以 mTOR 和 InsP3R 活性依赖性方式增加自噬诱导 (P<0.05)。短时间暴露于异丙酚会充分激活 InsP3-1，为细胞保护提供足够的自噬，而长时间暴露于异丙酚会通过 InsP3-1 过度激活而损害自噬流，从而诱导细胞凋亡。异丙酚会损伤线粒体并减少胞质 ATP。全麻药对细胞凋亡和自噬的影响是紧密结合的；两者都是由 1 型 InsP3R 的差异激活引起的。
General anesthetics are both neuroprotective and neurotoxic with unclear mechanisms. General anesthetics may control cell survival via their effects on autophagy by activation of type 1 inositol triphosphate receptor (InsP3R-1). DT40 or SH-SY5Y cells with only or over 99% expression of InsP3R-1 were treated with isoflurane or propofol. Cell viability was determined by MTT reduction or LDH release assays. Apoptosis was determined by measuring Caspase-3 or by TUNEL assay. Autophagy activity was determined by measuring LC3 II and P62. We evaluated mitochondrial integrity using MitoTracker Green and cytosolic ATP levels. Fura2-AM was used to measure the concentrations of cytosolic calcium ([Ca2+]c). Propofol significantly increased peak and integrated calcium response (P < 0.001) in cells with InsP3R-1 but not in cells with triple knockout of InsP3R. Both propofol and isoflurane increased autophagy induction (P < 0.05) in an mTOR- and InsP3R- activity dependent manner. Short exposure to propofol adequately activated InsP3-1 to provide sufficient autophagy for cytoprotection, while prolonged exposure to propofol induced cell apoptosis via impairment of autophagy flux through over activation of InsP3-1. Propofol damaged mitochondria and decreased cytosolic ATP. The effects of general anesthetics on apoptosis and autophagy are closely integrated; both are caused by differential activation of the type 1 InsP3R.
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影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
影响因子：
8.8
作者：
Bickler, PE;Zhan, XH;Fahlman, CS
通讯作者：
Fahlman, CS
影响因子：
5.7
作者：
Cattano, Davide;Young, Chainllie;Olney, John W.
通讯作者：
Olney, John W.
影响因子：
8.8
作者：
Liang G;Ward C;Peng J;Zhao Y;Huang B;Wei H
通讯作者：
Wei H
影响因子：
3.2
作者：
Cree, IA;Andreotti, PE
通讯作者：
Andreotti, PE