GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes

Eunsook Lee, Marta Sidoryk-Wêgrzynowicz, Ning Wang, Anton Webb, Deok Soo Son, Kyuwon Lee, Michael Aschner

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

The G protein-coupled estrogen receptor GPR30 contributes to the neuroprotective effects of 17β-estradiol (E2); however, the mechanisms associated with this protection have yet to be elucidated. Given that E2 increases astrocytic expression of glutamate transporter-1 (GLT-1), which would prevent excitotoxic-induced neuronal death, we proposed that GPR30 mediates E2 action on GLT-1 expression. To investigate this hypothesis, we examined the effects of G1, a selective agonist of GPR30, and GPR30 siRNA on astrocytic GLT-1 expression, as well as glutamate uptake in rat primary astrocytes, and explored potential signaling pathways linking GPR30 to GLT-1. G1 increased GLT-1 protein and mRNA levels, subject to regulation by both MAPK and PI3K signaling. Inhibition of TGF-α receptor suppressed the G1-induced increase in GLT-1 expression. Silencing GPR30 reduced the expression of both GLT-1 and TGF-α and abrogated the G1-induced increase in GLT-1 expression. Moreover, the G1-induced increase in GLT-1 protein expression was abolished by a protein kinase A inhibitor and an NF-κB inhibitor. G1 also enhanced cAMP response element-binding protein (CREB), as well as both NF-κB p50 and NF-κB p65 binding to the GLT-1 promoter. Finally, to model dysfunction of glutamate transporters, manganese was used, and G1 was found to attenuate manganese-induced impairment in GLT-1 protein expression and glutamate uptake. Taken together, the present data demonstrate that activation of GPR30 increases GLT-1 expression via multiple pathways, suggesting that GPR30 is worthwhile as a potential target to be explored for developing therapeutics of excitotoxic neuronal injury.

Original languageEnglish (US)
Pages (from-to)26817-26828
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number32
DOIs
StatePublished - Aug 3 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes'. Together they form a unique fingerprint.

  • Cite this

    Lee, E., Sidoryk-Wêgrzynowicz, M., Wang, N., Webb, A., Son, D. S., Lee, K., & Aschner, M. (2012). GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes. Journal of Biological Chemistry, 287(32), 26817-26828. https://doi.org/10.1074/jbc.M112.341867