Transforming growth factor-α mediates estrogen-induced upregulation of glutamate transporter GLT-1 in rat primary astrocytes
Article first published online: 7 APR 2012
Copyright © 2012 Wiley Periodicals, Inc.
Volume 60, Issue 7, pages 1024–1036, July 2012
How to Cite
Lee, E., Sidoryk-Wegrzynowicz, M., Yin, Z., Webb, A., Son, D.-S. and Aschner, M. (2012), Transforming growth factor-α mediates estrogen-induced upregulation of glutamate transporter GLT-1 in rat primary astrocytes. Glia, 60: 1024–1036. doi: 10.1002/glia.22329
- Issue published online: 8 MAY 2012
- Article first published online: 7 APR 2012
- Manuscript Accepted: 28 FEB 2012
- Manuscript Received: 19 DEC 2011
- NIH. Grant Numbers: NIGMS SC1 089630, NIEHS ES R01 10563
- glutamate uptake;
- glutamate transporter;
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.