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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. © 2012 Wiley Periodicals, Inc.
| Authors: | Lee, Eunsook; Sidoryk‐Wegrzynowicz, Marta; Yin, Zhaobao; Webb, Anton; Son, Deok‐Soo; Aschner, Michael | |
| Journal: | Glia | |
| Volume: | 60 | |
| Issue: | 7 | |
| Year: | 2012 | |
| Pages: | 1024 | |
| DOI: | 10.1002/glia.22329 | |
| Publication date: | 01-07-2012 |
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