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

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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

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Amino Acid Transport System X-AG
Astrocytes
Rats
Manganese
Glutamic Acid
Cyclic AMP Response Element-Binding Protein
Proteins
Neuroprotective Agents
Protein Kinase Inhibitors
G-Protein-Coupled Receptors
Cyclic AMP-Dependent Protein Kinases
Phosphatidylinositol 3-Kinases
GTP-Binding Proteins
Estrogen Receptors
Small Interfering RNA

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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

GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes. / Lee, Eunsook; Sidoryk-Wêgrzynowicz, Marta; Wang, Ning; Webb, Anton; Son, Deok Soo; Lee, Kyuwon; Aschner, Michael.

In: Journal of Biological Chemistry, Vol. 287, No. 32, 03.08.2012, p. 26817-26828.

Research output: Contribution to journalArticle

Lee, E, Sidoryk-Wêgrzynowicz, M, Wang, N, Webb, A, Son, DS, Lee, K & Aschner, M 2012, 'GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes', Journal of Biological Chemistry, vol. 287, no. 32, pp. 26817-26828. https://doi.org/10.1074/jbc.M112.341867
Lee E, Sidoryk-Wêgrzynowicz M, Wang N, Webb A, Son DS, Lee K et al. GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes. Journal of Biological Chemistry. 2012 Aug 3;287(32):26817-26828. https://doi.org/10.1074/jbc.M112.341867
Lee, Eunsook ; Sidoryk-Wêgrzynowicz, Marta ; Wang, Ning ; Webb, Anton ; Son, Deok Soo ; Lee, Kyuwon ; Aschner, Michael. / GPR30 regulates glutamate transporter GLT-1 expression in rat primary astrocytes. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 32. pp. 26817-26828.
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