ATP-sensitive potassium channel opener iptakalim protected against the cytotoxicity of MPP+ on SH-SY5Y cells by decreasing extracellular glutamate level
ATP-sensitive potassium channel opener iptakalim protected against the cytotoxicity of MPP+ on SH-SY5Y cells by decreasing extracellular glutamate level
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DOI：
10.1111/j.1471-4159.2005.03306.x
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发表时间：
2005-09-01
影响因子：
4.7
通讯作者：
Hu, G
中科院分区：
文献类型：
--
作者：
Hu, LF;Wang, S;Hu, G
越来越多的证据表明，ATP敏感性钾（K-ATP）通道开放剂（KCOs）在体内和体外的帕金森病（PD）模型中发挥显着的神经保护作用。然而，其机制并不十分清楚。在本研究中，我们证明SH-SY 5 Y细胞表达K-ATP通道的Kir6.1，Kir6.2，SUR 1和SUR 2亚基的mRNA和蛋白。此外，我们的研究结果表明，1-甲基-4-苯基-吡啶离子（MPP+）诱导上调mRNA的Kir6.2亚基和下调SUR 1。进一步发现，用新型K-ATP通道开放剂埃他卡林预处理可以减轻MPP+暴露后SH-SY 5 Y细胞培养物中细胞外谷氨酸水平的升高和细胞存活率的降低。谷氨酸转运体抑制剂反式吡咯烷-2，4-二羧酸（trans-pyrrolidine-2，4-dicarboxylic acid，t-PDC）部分阻断埃他卡林降低细胞外谷氨酸水平的作用。此外，埃他卡林防止MPP+诱导的抑制谷氨酸摄取的原代培养的星形胶质细胞。选择性线粒体K-ATP（mitoK（ATP））通道阻断剂5-HD可阻断埃他卡林对星形胶质细胞谷氨酸摄取的促进作用。这些结果表明：（i）K-ATP通道功能障碍可能参与MPP+诱导的细胞毒性机制;（ii）埃他卡林可能通过开放mitoK（ATP）通道调节谷氨酸转运体，从而减轻MPP+诱导的细胞外谷氨酸水平的升高，从而保护SH-SY 5 Y细胞免受MPP+诱导的细胞毒性。
Mounting evidence reveals that ATP-sensitive potassium (K-ATP) channel openers (KCOs) exert significant neuroprotection in vivo and in vitro in several models of Parkinson's disease (PD). However, the mechanisms are not well understood. In this study, we demonstrated that SH-SY5Y cells expressed mRNA and proteins for Kir6.1, Kir6.2, SUR1 and SUR2 subunits of K-ATP channels. Moreover, our results showed that 1-methyl-4-phenyl-pyridinium ion (MPP+) induced up-regulation of mRNA for the Kir6.2 subunit and down-regulation of SUR1. It was further found that pretreatment with iptakalim, a novel K-ATP channel opener, could attenuate increased extracellular glutamate level and decreased cell survival in SH-SY5Y cell culture after exposure to MPP+. Trans-pyrrolidine-2, 4-dicarboxylic acid (t-PDC), a glutamate transporter inhibitor, partially blocked the effect of iptakalim decreasing extracellular glutamate level. Additionally, iptakalim prevented MPP+-induced inhibition of glutamate uptake in primary cultured astrocytes. The beneficial effects of iptakalim on glutamate uptake of astrocytes were abolished by selective mitochondrial K-ATP (mitoK(ATP)) channel blocker 5-HD. These results suggest (i) K-ATP channel dysfunction may be involved in the mechanisms of MPP+-induced cytotoxicity and (ii) iptakalim may modulate glutamate transporters and subsequently alleviate the increase of extracellular glutamate levels induced by MPP+ through opening mitoK(ATP) channels, thereby protecting SH-SY5Y cells against MPP+-induced cytotoxicity.