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Text
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URL Address
<a href="http://doi.org/10.1016/j.neuropharm.2017.07.020" target="_blank" rel="noreferrer noopener">http://doi.org/10.1016/j.neuropharm.2017.07.020</a>
Pages
189–196
Volume
125
Dublin Core
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Title
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Valproate increases dopamine transporter expression through histone acetylation and enhanced promoter binding of Nurr1.
Publisher
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Neuropharmacology
Date
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2017
2017-10
Subject
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Acetylation/drug effects; Animals; Butyrates/pharmacology; Cell Line; Cell Survival/drug effects; Dopamine Plasma Membrane Transport Proteins/*metabolism; Dopamine transporter; Dopaminergic Neurons/cytology/drug effects/metabolism; Dose-Response Relationship; Drug; Epigenesis; Epigenetics; Genetic; Genetic/drug effects; Group A; HDAC; Histone deacetylase; Histone Deacetylase Inhibitors/*pharmacology; Histone Deacetylases/metabolism; Histones/*drug effects/metabolism; Homeodomain Proteins/metabolism; Hydroxamic Acids/pharmacology; Member 2/*metabolism; Messenger/metabolism; Nuclear Receptor Subfamily 4; Nurr1; Pitx3; Promoter Regions; Rats; RNA; Transcription Factors/metabolism; Valproate; Valproic Acid/*pharmacology
Creator
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Green Ashley L; Zhan Le; Eid Aseel; Zarbl Helmut; Guo Grace L; Richardson Jason R
Description
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The dopamine transporter (DAT) is the key regulator of dopaminergic transmission and is a target of several xenobiotics, including pesticides and pharmacological agents. Previously, we identified a prominent role for histone deacetylases in the regulation of DAT expression. Here, we utilized a rat dopaminergic cell line (N27) to probe the responsiveness of DAT mRNA expression to inhibitors of histone acetylation. Inhibition of histone deacetylases (HDACs) by valproate, butyrate and Trichostatin A led to a 3-10-fold increase in DAT mRNA expression, a 50% increase in protein levels, which were accompanied by increased H3 acetylation levels. To confirm the mechanism of valproate-mediated increase in DAT mRNA, chromatin immunoprecipitation (ChIP) assays were used and demonstrated a significant increase in enrichment of acetylation of histone 3 on lysines 9 and 14 (H3K9/K14ac) in the DAT promoter. Expression of Nurr1 and Pitx3, key regulators of DAT expression, were increased following valproate treatment and Nurr1 binding was enriched in the DAT promoter. Together, these results indicate that histone acetylation and subsequent enhancement of transcription factor binding are plausible mechanisms for DAT regulation by valproate and, perhaps, by other xenobiotics.
Identifier
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<a href="http://doi.org/10.1016/j.neuropharm.2017.07.020" target="_blank" rel="noreferrer noopener">10.1016/j.neuropharm.2017.07.020</a>
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
2017
Acetylation/drug effects
Animals
Butyrates/pharmacology
Cell Line
Cell Survival/drug effects
Department of Pharmaceutical Sciences
Dopamine Plasma Membrane Transport Proteins/*metabolism
Dopamine transporter
Dopaminergic Neurons/cytology/drug effects/metabolism
Dose-Response Relationship
Drug
Eid Aseel
Epigenesis
Epigenetics
Genetic
Genetic/drug effects
Green Ashley L
Group A
Guo Grace L
HDAC
Histone deacetylase
Histone Deacetylase Inhibitors/*pharmacology
Histone Deacetylases/metabolism
Histones/*drug effects/metabolism
Homeodomain Proteins/metabolism
Hydroxamic Acids/pharmacology
Member 2/*metabolism
Messenger/metabolism
NEOMED College of Pharmacy
Neuropharmacology
Nuclear Receptor Subfamily 4
Nurr1
Pitx3
Promoter Regions
Rats
Richardson Jason R
RNA
Transcription Factors/metabolism
Valproate
Valproic Acid/*pharmacology
Zarbl Helmut
Zhan Le