Transforming growth factor-α mediates estrogen-induced upregulation of glutamate transporter GLT-1 in rat primary astrocytes

Eunsook Lee, Marta Sidoryk-Wegrzynowicz, Zhaobao Yin, Anton Webb, Deok Soo Son, Michael Aschner

Research output: Contribution to journalArticle

43 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1024-1036
Number of pages13
JournalGlia
Volume60
Issue number7
DOIs
StatePublished - Jul 1 2012
Externally publishedYes

Keywords

  • 17β-estradiol
  • Astrocytes
  • GLT-1
  • Glutamate transporter
  • Glutamate uptake
  • Manganese
  • TGF-α
  • Tamoxifen

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

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