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Heterogeneity and potentiation of AMPA type of glutamate receptors in rat cultured microglia
Author(s) -
Hagino Yukiko,
Kariura Yukihiro,
Manago Yoshimasa,
Amano Taiju,
Wang Bing,
Sekiguchi Masayuki,
Nishikawa Kaori,
Aoki Shunsuke,
Wada Keiji,
Noda Mami
Publication year - 2004
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20034
Subject(s) - ampa receptor , long term potentiation , biology , glutamate receptor , receptor , microglia , allosteric regulation , long term depression , microbiology and biotechnology , pharmacology , neuroscience , biochemistry , immunology , inflammation
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 Ca 2+ 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. © 2004 Wiley‐Liss, Inc.