Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription
Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription
复制标题
腺苷受体 A1-A2a 异质体通过 YY1 诱导的 PPARγ 转录抑制调节 EAAT2 表达和谷氨酸摄取
DOI：
10.1155/2020/2410264
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发表时间：
2020-03-06
期刊：
影响因子：
2.9
通讯作者：
Gui, Li
中科院分区：
文献类型：
--
作者：
Hou, Xianhua;Li, Yuan;Gui, Li
腺苷受体A1（A1 AR）和A2 a（A2 aAR）在调节谷氨酸摄取以避免引起脑中兴奋性毒性的谷氨酸积累中起重要作用;然而，A1 AR和A2 aAR的作用的精确机制尚不清楚。在此，我们报告，A1 AR蛋白在星形胶质细胞膜和细胞内谷氨酸的水平的表达下降，而A2 aR蛋白的表达升高暴露于氧-葡萄糖剥夺（OGD）条件下的细胞。免疫共沉淀（Co-IP）实验表明，在OGD条件下，A1 AR与A2 aAR相互作用。2-氯-N6-环戊基腺苷（CCPA）和SCH 58251分别激活A1 AR和灭活A2 aAR，可部分逆转OGD介导的谷氨酸摄取功能障碍，升高EAAT 2和PPARγ蛋白水平，并抑制阴阳1（YY 1）的表达。YY 1的沉默和PPARγ的激活均上调EAAT 2的表达。此外，YY 1沉默在正常和OGD条件下均升高了PPARγ水平。组蛋白去乙酰化酶（HDAC）1与YY 1相互作用，沉默HDAC 1可提高PPARγ启动子活性。综上所述，我们的研究结果表明，A1 AR-A2 aAR异聚体通过YY 1介导的HDAC 1向PPARγ启动子区域的募集来调节EAAT 2表达和谷氨酸摄取。
Adenosine receptors A1 (A1AR) and A2a (A2aAR) play an important role in regulating glutamate uptake to avoid glutamate accumulation that causes excitotoxicity in the brain; however, the precise mechanism of the effects of A1AR and A2aAR is unclear. Herein, we report that expression of the A1AR protein in the astrocyte membrane and the level of intracellular glutamate were decreased, while expression of the A2aR protein was elevated in cells exposed to oxygen-glucose deprivation (OGD) conditions. Coimmunoprecipitation (Co-IP) experiments showed that A1AR interacts with A2aAR under OGD conditions. The activation of A1AR and inactivation of A2aAR by 2-chloro-N6-cyclopentyladenosine (CCPA) and SCH58251, respectively, partly reversed OGD-mediated glutamate uptake dysfunction, elevated EAAT2, and PPARγ protein levels, and suppressed the expression of Ying Yang 1 (YY1). Both the silencing of YY1 and the activation of PPARγ upregulated EAAT2 expression. Moreover, YY1 silencing elevated the PPARγ level under both normal and OGD conditions. Histone deacetylase (HDAC)1 was found to interact with YY1, and HDAC1 silencing improved PPARγ promoter activity. Taken together, our findings suggest that A1AR-A2aAR heteromers regulate EAAT2 expression and glutamate uptake through the YY1-mediated recruitment of HDAC1 to the PPARγ promoter region.