Valproate-dependent transcriptional regulation of GLAST/EAAT1 expression:: Involvement of Ying-Yang 1

被引:35
作者
Aguirre, Gisela [1 ]
Rosas, Sandra [1 ]
Lopez-Bayghen, Esther [1 ]
Otega, Arturo [1 ]
机构
[1] Inst Politecn Nacl, CINVESTAV, IPN,Ctr Invest & Estudios Avanzados, Dept Genet & Biol Mol, Mexico City 07000, DF, Mexico
关键词
glutamate transporters; valproate; Bergmann glia; iHDAC; histone; epilepsy;
D O I
10.1016/j.neuint.2008.01.015
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Valproate, a widely used anti-epileptic drug also employed in the treatment of neurological diseases such as bipolar disorder and migraine, regulates the glutamatergic and GABAergic systems, although its effects in cell physiology have not been thoroughly characterized. High concentrations of glutamate reached during abnormal neurotransmission if not removed properly, become neurotoxic. Glutamate clearance is carried out by high affinity Na+-dependent glutamate transporter systems. The glutamate/aspartate transporter GLAST/EAAT1 plays the major role in glutamate removal and is regulated at different levels: transcription, post-translational modifications and cytoplasmic trafficking. The aim of this work was to gain insight into a plausible effect of valproate in GLAST function. Using cultured Bergmann glia cells from chick cerebellum we demonstrate here that valproate exposure elicits a dual regulatory effect on GLAST. In the short-term, valproate increases its Na+-dependent [3 HI-D-aspartate uptake activity in a cytochalasin B-sensitive manner. Interestingly, a synergism between valproate and a histone deacetylase inhibitor was observed. Long-term valproate treatment up-regulates chglast promoter activity, GLAST mRNA levels, GLAST molecules at the plasma membrane and its uptake activity. Furthermore, valproate induces histone 3 lysine 14 acetylation and regulates Ying-Yang 1 (YY1) transcriptional repression on the chglast promoter. These results suggest that valproate elicits its effect through its histone deacetylase inhibitor properties. (C) 2008 Elsevier Ltd. All rights reserved.
引用
收藏
页码:1322 / 1331
页数:10
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