Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia

Yukiko Hagino, Yukihiro Kariura, Yoshimasa Manago, Taiju Amano, Bing Wang, Masayuki Sekiguchi, Kaori Nishikawa, Shunsuke Aoki, Keiji Wada, Mami Noda

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62 Citations (Scopus)

Abstract

α-amino-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) receptor in rat cultured microglia were analyzed precisely using flop- and flip-preferring allosteric modulators of AMPA receptors, 4-[2- (phenylsulfonylamino)ethylthio]- 2,6-difluoro-phenoxyacetamide (PEPA) and cyclothiazide (CTZ), respectively. Glutamate (Glu)- or kainite (KA)-induced currents were completely inhibited by a specific blocker of AMPA receptor, LY300164, indicating that functional Glu-receptors in cultured microglia are mostly AMPA receptor but not KA receptor in many cells. Glu- and KA-induced currents were potentiated by PEPA and CTZ in a concentration-dependent manner. The ratio of the potentiation by PEPA to the potentiation by cyclothiazide varied with cells between 0.1 and 0.9, suggesting cell-to-cell heterogeneity of AMPA receptor subunits expressed in microglia. Quantitative RT-PCR revealed that GluR1-3 mainly occurred in the flip forms, which agreed with the stronger potentiation of receptor currents by CTZ vs. PEPA. Finally, the potentiation of microglial AMPA receptors by PEPA and CTZ inhibited the Glu-induced release of tumor necrosis factor-α (TNF-α) unpredictably. The increase in TNF-α release by Glu or KA required extracellular Na+ and Ca2+ ions but not mitogen-activated protein kinase (MAPK), suggesting the effects of PEPA and CTZ were not due to the inhibition of MAPK. These results suggest that potentiation of microglial AMPA receptors serves as a negative feedback mechanism for the regulation of TNF-α release and may contribute to the ameliorating effects of allosteric modulators of AMPA receptors.

Original languageEnglish
Pages (from-to)68-77
Number of pages10
JournalGLIA
Volume47
Issue number1
DOIs
Publication statusPublished - Jul 1 2004

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience

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    Hagino, Y., Kariura, Y., Manago, Y., Amano, T., Wang, B., Sekiguchi, M., Nishikawa, K., Aoki, S., Wada, K., & Noda, M. (2004). Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia. GLIA, 47(1), 68-77. https://doi.org/10.1002/glia.20034