Mechanism of raloxifene-induced upregulation of glutamate transporters in rat primary astrocytes.
Mechanism of raloxifene-induced upregulation of glutamate transporters in rat primary astrocytes.
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作者：
Karki, Pratap;Webb, Anton;Zerguine, Abdelbassat;Choi, Joseph;Son, Deok-Soo;Lee, Eunsook
雷洛昔芬（RX）是一种选择性雌激素受体调节剂（SERM），在多种临床和实验环境中发挥神经保护作用。星形胶质细胞谷氨酸转运体GLT-1（EAAT 2）和GLAST（EAAT 1）是中枢神经系统中主要的谷氨酸转运体，从突触间隙摄取大部分过量的谷氨酸以防止兴奋性毒性神经元死亡。由于靶向星形胶质细胞谷氨酸转运蛋白以增强其表达和功能的药物代表了兴奋性毒性相关神经退行性疾病的潜在治疗方法，因此我们检测了RX是否调节大鼠原代星形胶质细胞中GLT-1和GLAST的表达和功能。结果表明，RX可显著增加谷氨酸摄取和GLT-1 mRNA及蛋白水平的表达。RX通过激活多种信号通路（包括雌激素受体（ER）ER-α、ER-β和GPR 30介导的ERK、EGFR和CREB）增强GLT-1表达。在转录水平，NF-κB在RX诱导的GLT-1表达中起关键作用，因为RX增加NF-κB报告基因活性并诱导NF-κB p65和p50与GLT-1启动子结合。RX减弱了锰（Mn）诱导的GLT-1表达和谷氨酸摄取的减少，锰（Mn）的慢性高水平暴露导致锰中毒。RX还通过NF-κB通路和ER增加其启动子活性和蛋白水平上调GLAST。我们的研究结果提供了新的见解，RX诱导的GLT-1和GLAST表达增强的机制，以及锰减少这些转运蛋白的表达衰减。这些发现对于开发与受损的星形胶质细胞谷氨酸转运蛋白相关的神经退行性疾病的治疗方法具有重要价值。
Raloxifene (RX), a selective estrogen receptor modulator (SERM), exerts neuroprotection in multiple clinical and experimental settings. Astrocytic glutamate transporters GLT-1 (EAAT2) and GLAST (EAAT1) are the main glutamate transporters in the central nervous system, taking up most of excess glutamate from the synaptic cleft to prevent excitotoxic neuronal death. Since drugs targeting astrocytic glutamate transporters to enhance their expression and function represent potential therapeutics for neurodegenerative disorders associated with excitotoxicity, we tested if RX modulates the expression and function of GLT-1 and GLAST in rat primary astrocytes. The results showed that RX significantly increased glutamate uptake and expression of GLT-1 mRNA and protein levels. RX enhanced GLT-1 expression by the activation of multiple signaling pathways including ERK, EGFR and CREB mediated by estrogen receptors (ERs) ER-α, ER-β and GPR30. At the transcriptional level, NF-κB played a critical role in RX-induced GLT-1 expression as RX increased NF-κB reporter activity and induced binding of NF-κB p65 and p50 to the GLT-1 promoter. RX attenuated the reduction of GLT-1 expression and glutamate uptake induced by manganese (Mn) whose chronic high levels of exposure cause manganism. RX also upregulated GLAST by increasing its promoter activity and protein levels via the NF-κB pathway and ERs. Our findings provide new insight into the mechanism of RX-induced enhancement of GLT-1 and GLAST expression, as well as the attenuation of Mn-reduced expression of these transporters. These findings will be highly valuable for developing therapeutics of neurodegenerative diseases associated with impaired astrocytic glutamate transporters.
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影响因子：
6.2
作者：
Cerciat, M.;Unkila, M.;Arevalo, M. -A.
通讯作者：
Arevalo, M. -A.
影响因子：
5.3
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Baltan, Selva;Murphy, Sean P.;Morrison, Richard S.
通讯作者：
Morrison, Richard S.
影响因子：
6.2
作者：
Fattorini, Giorgia;Melone, Marcello;Conti, Fiorenzo
通讯作者：
Conti, Fiorenzo
影响因子：
2.6
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Fang, Ming;Wu, Xin-Chi;Huang, Wenlong
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Huang, Wenlong
影响因子：
5
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Abdelhamid, Ramy;Luo, Jia;VandeVrede, Lawren;Kundu, Indraneel;Michalsen, Bradley;Litosh, Vladislav A.;Schiefer, Isaac T.;Gherezghiher, Teshome;Yao, Ping;Qin, Zhihui;Thatcher, Gregory R. J.
通讯作者：
Thatcher, Gregory R. J.