ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2009
The gad2 promoter is a transcriptional target of estrogen receptor (ER)alpha and ER beta: a unifying hypothesis to explain diverse effects of estradiol.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 56 citations in OpenAlex.
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- Thyroid Hormone Neuroprotection Against Perfluorooctane Sulfonic Acid Cholinergic and Glutamatergic Disruption and Neurodegeneration Induction.Biomedicines · 2024Article
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- Bisphenol-A Neurotoxic Effects on Basal Forebrain Cholinergic Neurons In Vitro and In Vivo.Biology · 2023Article
- Glutamatergic and GABAergic neurons in the preoptic area of the hypothalamus play key roles in menopausal hot flashes.Frontiers in aging neuroscience · 2022Article
- Neuroprotective Action of Multitarget 7-Aminophenanthridin-6(ACS chemical neuroscience · 2021Article
- Estradiol Acts in Lateral Thalamic Region to Attenuate Varicella Zoster Virus Associated Affective Pain.Neuroscience · 2019Article
- Sex-specific Behavioral Features of Rodent Models of Autism Spectrum Disorder.Experimental neurobiology · 2018Review
- GAD65 Promoter Polymorphism rs2236418 Modulates Harm Avoidance in Women via Inhibition/Excitation Balance in the Rostral ACC.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2018Article
- Effect of Pregnancy on TMJ Nociception in Rats.Kou qiang yi xue yan jiu = Journal of oral science research · 2018Article
- Aromatase Derived Estradiol Within the Thalamus Modulates Pain Induced by Varicella Zoster Virus.Frontiers in integrative neuroscience · 2018Article
- Genes in the GABA Pathway Increase in the Lateral Thalamus of Sprague-Dawley Rats During the Proestrus/Estrus Phase.Journal of cellular physiology · 2016Article
- Interictal spike frequency varies with ovarian cycle stage in a rat model of epilepsy.Experimental neurology · 2015Article
- Resting state alpha frequency is associated with menstrual cycle phase, estradiol and use of oral contraceptives.Brain research · 2014Article
- GABAergic influence on temporomandibular joint-responsive spinomedullary neurons depends on estrogen status.Neuroscience · 2014Article
- Estrogenic modulation of auditory processing: a vertebrate comparison.Frontiers in neuroendocrinology · 2013Review
- Gender-specific effect of Mthfr genotype and neonatal vigabatrin interaction on synaptic proteins in mouse cortex.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2011Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Estradiol (E(2)) regulates a wide range of neural functions, many of which require activation of estrogen receptor alpha (ERalpha) and/or ERbeta, ligand-gated transcriptional regulators. Surprisingly, very few neural gene targets of ERs have been identified, and these cannot easily explain the myriad effects of E(2). GABA regulates most of the same neural functions as E(2), and GABAergic neurons throughout the brain contain ER. Therefore, we examined whether E(2) directly regulates expression of glutamic acid decarboxylase 2 (gad2), the enzyme primarily responsible for GABA synthesis for synaptic release. Using dual luciferase assays, we found that E(2), but not other gonadal steroids, stimulated the activity of a 2691 bp rat gad2 promoter reporter construct. Activation required either ERalpha or ERbeta, and ERbeta did not repress ERalpha-mediated transactivation. Site-directed mutagenesis studies identified three estrogen response elements (EREs) with cell-specific functions. An ERE at -711 upstream of the gad2 translational start site was essential for transactivation in both MCF-7 breast cancer cells and SN56.B5.G4 neural cells, but an ERE at -546 enhanced transcription only in neural cells. A third ERE at -1958 was inactive in neural cells but exerted potent transcriptional repression in E(2)-treated MCF-7 cells. Chromatin immunoprecipitation assays in mouse GABAergic N42 cells confirmed that E(2) induced ERalpha binding to a DNA fragment containing sequences corresponding to the -546 and -711 EREs of the rat promoter. Based on these data, we propose that direct transcriptional regulation of gad2 may explain, at least in part, the ability of E(2) to impact such a diverse array of neural functions.
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