title: Valproate-dependent transcriptional regulation of GLAST/EAAT1 expression: involvement of Ying-Yang 1.
abstract: 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)H]-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.
authors.affiliation: Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Cinvestav-IPN, Apartado Postal 14-740, México, D.F. 07000, Mexico.
authors.forename: Gisela
authors.initials: G
authors.lastname: Aguirre
authors.forename: Sandra
authors.initials: S
authors.lastname: Rosas
authors.forename: Esther
authors.initials: E
authors.lastname: López-Bayghen
authors.forename: Arturo
authors.initials: A
authors.lastname: Ortega
mesh_terms: D000107:Acetylation; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001224:Aspartic Acid / Q000378:metabolism; D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D027341:Excitatory Amino Acid Transporter 1 / Q000096:biosynthesis*; D005786:Gene Expression Regulation / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012964:Sodium / Q000502:physiology; D013268:Stimulation, Chemical; D014635:Valproic Acid / Q000494:pharmacology*; D050986:YY1 Transcription Factor / Q000235:genetics / Q000502:physiology*
chemical_list: D000927:Anticonvulsants; D027341:Excitatory Amino Acid Transporter 1; D006657:Histones; D050986:YY1 Transcription Factor; D001224:Aspartic Acid; D014635:Valproic Acid; D012964:Sodium