KATP channel openers facilitate glutamate uptake by GluTs in rat primary cultured Astrocytes
KATP channel openers facilitate glutamate uptake by GluTs in rat primary cultured Astrocytes
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DOI：
10.1038/sj.npp.1301501
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发表时间：
2008-05-01
影响因子：
7.6
通讯作者：
Hu, Gang
中科院分区：
文献类型：
--
作者：
Sun, Xiu-Lan;Zeng, Xiao-Ning;Hu, Gang
包括我们实验室在内的越来越多的证据表明，在体内和体外，ATP敏感性钾通道(K-ATP通道)的开放都起到了神经元保护作用。因此，K-ATP通道开放剂(KCO)被认为是一种潜在的神经保护剂。我们以前的研究表明，K-ATP通道可以调节PC12细胞和大鼠突触体内的谷氨酸摄取活性。由于星形胶质细胞的谷氨酸转运体(Gluts)在谷氨酸摄取中起着关键作用，而且KATP通道也在星形胶质细胞中表达，本研究探讨了KATP通道是否以及如何调节原代培养的星形胶质细胞中Glug的功能。结果表明，除肌膜KCO P1075外，非选择性KCO匹那地尔、选择性线粒体KCO二氮卓、新型KCO和血脑屏障通透性KCO埃他卡林均可促进谷氨酸摄取。此外，吡那地尔、二氮卓和埃他卡林可逆转1-甲基-4-苯基吡啶(MPP+)对谷氨酸摄取的抑制作用。这些增强作用可被线粒体K-ATP阻断剂5-羟基癸酸完全消除。此外，二氮嗪或埃他卡林均能抑制MPP+诱导的ROS升高和蛋白激酶C(PKC)的磷酸化。这些发现首次证明K-ATP通道，尤其是线粒体K-ATP通道的激活，通过减少ROS的产生和下调PKC的磷酸化，改善了星形胶质细胞中GUTS的功能。因此，本研究不仅揭示了KCOs作为谷氨酸调节剂的新的药理作用，而且为神经保护提供了新的策略。
Increasing evidence, including from our laboratory, has revealed that opening of ATP sensitive potassium channels (K-ATP channels) plays the neuronal protective roles both in vivo and in vitro. Thus K-ATP channel openers (KCOs) have been proposed as potential neuroprotectants. Our previous studies demonstrated that K-ATP channels could regulate glutamate uptake activity in PC12 cells as well as in synaptosomes of rats. Since glutamate transporters (GluTs) of astrocytes play crucial roles in glutamate uptake and KATP channels are also expressed in astrocytes, the present study showed whether and how KATP channels regulated the function of GluTs in primary cultured astrocytes. The results showed that nonselective KCO pinacidil, selective mitochondrial KCO diazoxide, novel, and blood-brain barrier permeable KCO iptakalim could enhance glutamate uptake, except for the sarcolemmal KCO P1075. Moreover pinacidil, diazoxide, and iptakalim reversed the inhibition of glutamate uptake induced by 1-methyl-4-phenylpyridinium ( MPP+). These potentiated effects were completely abolished by mitochondrial K-ATP blocker 5-hydroxydecanoate. Furthermore, either diazoxide or iptakalim could inhibit MPP+ -induced elevation of reactive oxygen species (ROS) and phosphorylation of protein kinases C (PKC). These findings are the first to demonstrate that activation of K-ATP channel, especially mitochondrial K-ATP channel, improves the function of GluTs in astrocytes due to reducing ROS production and downregulating PKC phosphorylation. Therefore, the present study not only reveals a novel pharmacological profile of KCOs as regulators of GluTs, but also provides a new strategy for neuroprotection.