title: Transforming growth factor-α mediates estrogen-induced upregulation of glutamate transporter GLT-1 in rat primary astrocytes.
abstract: Glutamate transporter-1 (GLT-1) plays a central role in preventing excitotoxicity by removing excess glutamate from the synaptic clefts. 17β-Estradiol (E2) and tamoxifen (TX), a selective estrogen receptor (ER) modulator, afford neuroprotection in a range of experimental models. However, the mechanisms that mediate E2 and TX neuroprotection have yet to be elucidated. We tested the hypothesis that E2 and TX enhance GLT-1 function by increasing transforming growth factor (TGF)-α expression and, thus, attenuate manganese (Mn)-induced impairment in astrocytic GLT-1 expression and glutamate uptake in rat neonatal primary astrocytes. The results showed that E2 (10 nM) and TX (1 μM) increased GLT-1 expression and reversed the Mn-induced reduction in GLT-1, both at the mRNA and protein levels. E2/TX also concomitantly reversed the Mn-induced inhibition of astrocytic glutamate uptake. E2/TX activated the GLT-1 promoter and attenuated the Mn-induced repression of the GLT-1 promoter in astrocytes. TGF-α knockdown (siRNA) abolished the E2/TX effect on GLT-1 expression, and inhibition of epidermal growth factor receptor (TGF-α receptor) suppressed the effect of E2/TX on GLT-1 expression and GLT-1 promoter activity. E2/TX also increased TGF-α mRNA and protein levels with a concomitant increase in astrocytic glutamate uptake. All ERs (ER-α, ER-β, and G protein-coupled receptor 30) were involved in mediating E2 effects on the regulation of TGF-α, GLT-1, and glutamate uptake. These results indicate that E2/TX increases GLT-1 expression in astrocytes via TGF-α signaling, thus offering an important putative target for the development of novel therapeutics for neurological disorders.
authors.affiliation: Department of Physiology, Meharry Medical College, Nashville, TN 37208, USA. elee@mmc.edu
authors.forename: Eunsook
authors.initials: E
authors.lastname: Lee
authors.forename: Marta
authors.initials: M
authors.lastname: Sidoryk-Wegrzynowicz
authors.forename: Zhaobao
authors.initials: Z
authors.lastname: Yin
authors.forename: Anton
authors.initials: A
authors.lastname: Webb
authors.forename: Deok-Soo
authors.initials: DS
authors.lastname: Son
authors.forename: Michael
authors.initials: M
authors.lastname: Aschner
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D027342:Excitatory Amino Acid Transporter 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering; D051381:Rats; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D034741:RNA, Small Interfering; D020845:Selective Estrogen Receptor Modulators; C493395:Slc1a2 protein, rat; D016211:Transforming Growth Factor alpha; D013629:Tamoxifen; D004958:Estradiol; D066246:ErbB Receptors