Group I mGluR-Mediated Inhibition of Kir Channels Contributes to Retinal Muller Cell Gliosis in a Rat Chronic Ocular Hypertension Model
Group I mGluR-Mediated Inhibition of Kir Channels Contributes to Retinal Muller Cell Gliosis in a Rat Chronic Ocular Hypertension Model
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I 组 mGluR 介导的 Kir 通道抑制有助于视网膜 Mu
DOI：
10.1523/jneurosci.1291-12.2012
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发表时间：
2012-09-12
影响因子：
5.3
通讯作者：
Wang, Zhongfeng
中科院分区：
文献类型：
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作者：
Ji, Min;Miao, Yanying;Wang, Zhongfeng
Muller细胞胶质瘤的特征是胶质原纤维酸性蛋白（GFAP）的表达上调，是许多视网膜病理条件下的普遍反应。通常伴随GFAP表达增强的内向纠偏K+ (Kir)通道的下调是否有助于Muller细胞胶质瘤的发生尚不清楚。我们研究了大鼠慢性高眼压（COH）模型Muller细胞中Kir电流、GFAP和Kir4.1蛋白表达的变化，并探讨了Muller细胞胶质化的机制。我们发现，COH大鼠Muller细胞中的Kir电流和Kir4.1蛋白表达显著降低，而GFAP表达增加，这些变化被MPEP（一种I组代谢型谷氨酸受体（mGluR I）亚型mGluR5拮抗剂）消除。在正常分离的Muller细胞中，mGluR I激动剂(S)-3,5-二羟基苯基甘氨酸（DHPG）抑制Kir电流，而这种抑制作用被MPEP阻断。DHPG效应由细胞内Ca2+依赖性PLC/IP3-ryanodine/PKC信号通路介导，而cAMP-PKA通路不参与。此外，正常大鼠玻璃体内注射DHPG诱导Muller细胞的变化，与COH大鼠相似。dhpg诱导的Muller细胞中GFAP表达的增加被Ba2+阻断，提示Kir通道的参与。我们得出结论，COH大鼠中过量的细胞外谷氨酸过度激活mGluR5可能通过抑制Kir通道促进Muller细胞胶质瘤。
Muller cell gliosis, which is characterized by upregulated expression of glial fibrillary acidic protein (GFAP), is a universal response in many retinal pathological conditions. Whether down-regulation of inward rectifying K+ (Kir) channels, which commonly accompanies the enhanced GFAP expression, could contribute to Muller cell gliosis is poorly understood. We investigated changes of Kir currents, GFAP and Kir4.1 protein expression in Muller cells in a rat chronic ocular hypertension (COH) model, and explored the mechanisms underlying Muller cell gliosis. We show that Kir currents and Kir4.1 protein expression in Muller cells were reduced significantly, while GFAP expression was increased in COH rats, and these changes were eliminated by MPEP, a group I metabotropic glutamate receptors (mGluR I) subtype mGluR5 antagonist. In normal isolated Muller cells, the mGluR I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) suppressed the Kir currents and the suppression was blocked by MPEP. The DHPG effect was mediated by the intracellular Ca2+-dependent PLC/IP3-ryanodine/PKC signaling pathway, but the cAMP-PKA pathway was not involved. Moreover, intravitreal injection of DHPG in normal rats induced changes in Muller cells, similar to those observed in COH rats. The DHPG-induced increase of GFAP expression in Muller cells was obstructed by Ba2+, suggesting the involvement of Kir channels. We conclude that overactivation of mGluR5 by excessive extracellular glutamate in COH rats could contribute to Muller cell gliosis by suppressing Kir channels.