Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription
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 prote...
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| Language: | English |
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Wiley
2020-01-01
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| Series: | PPAR Research |
| Online Access: | http://dx.doi.org/10.1155/2020/2410264 |
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| author | Xianhua Hou Yuan Li Yuanyuan Huang Huan Zhao Li Gui |
| author_facet | Xianhua Hou Yuan Li Yuanyuan Huang Huan Zhao Li Gui |
| author_sort | Xianhua Hou |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-3a1d4c60b4a748fcab3c60b0d6e3f0c6 |
| institution | Kabale University |
| issn | 1687-4757 1687-4765 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
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| series | PPAR Research |
| spelling | doaj-art-3a1d4c60b4a748fcab3c60b0d6e3f0c62025-08-20T03:55:40ZengWileyPPAR Research1687-47571687-47652020-01-01202010.1155/2020/24102642410264Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ TranscriptionXianhua Hou0Yuan Li1Yuanyuan Huang2Huan Zhao3Li Gui4Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaDepartment of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaDepartment of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaDepartment of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaDepartment of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, ChinaAdenosine 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.http://dx.doi.org/10.1155/2020/2410264 |
| spellingShingle | Xianhua Hou Yuan Li Yuanyuan Huang Huan Zhao Li Gui Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription PPAR Research |
| title | Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription |
| title_full | Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription |
| title_fullStr | Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription |
| title_full_unstemmed | Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription |
| title_short | Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPARγ Transcription |
| title_sort | adenosine receptor a1 a2a heteromers regulate eaat2 expression and glutamate uptake via yy1 induced repression of pparγ transcription |
| url | http://dx.doi.org/10.1155/2020/2410264 |
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