Molecular pathways mediating activation by kainate of mitogen-activated protein kinase in oligodendrocyte progenitors

Oligodendroglial cells express ionotropic glutamate receptors of alpha-amin o-3-hydroxy-5-methyl-isoxazole-4-propionic acid hydrobromide (AMPA) and kai nate (KA) subtypes, Recently, we reported that AMPA receptor agonists incre ased Ca-45(2+) uptake and phospholipase C (PLC) activity. To further elucid ate the intracellular signaling mechanisms, we examined the effects of AMPA and KA on mitogen-activated protein kinase (MAPK). KA caused a time and co ncentration-dependent increase in MAPK activity (predominantly the p42(mapk ) Or ERK2) and the effect was blocked by 6-cyano-7-nitro-quinoxaline-2, 3-d ione (CNQX), a competitive AMPA/KA receptor antagonist. Furthermore, the no ncompetitive antagonists of AMPA receptor GYKI 52466 and LY 303070 prevente d the actions of the agonists, indicating that the effect of KA on MAPK act ivation is mediated through AMPA receptors in oligodendrocyte progenitors. Chelation of extracellular Ca2+ by EDTA or inhibition of PLC with U73122 ab olished MAPK activation by KA. In addition, KA-stimulated MAPK activation w as reduced by the protein kinase C (PKC) inhibitors, H7 and bisindolylmalei mide, as well as downregulation of PKC by prolonged exposure to phorbol est ers. The involvement of PKC in the signal transduction pathways was further supported by the ability of KA to induce translocation of PKC measured by [H-3]PDBu binding. Interestingly, a wortmannin-sensitive phosphatidylinosit ol 3-kinase and a pertussis toxin (PTX)-sensitive G protein form part of th e molecular pathways mediating MAPK activation by AMPA receptor. A specific inhibitor of MAPK kinase, PD 098059, blocked MAPK activation and reduced K A-induced c-fos gene expression. All together, these results indicate that MAPK is implicated in the transmission of AMPA signaling to the nucleus and requires extracellular Ca2+, and PLC/PKC activation. (C) 1999 Elsevier Sci ence B.V. All rights reserved.