Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways

L. Iacovelli, V. Bruno, L. Salvatore, D. Melchiorri, R. Gradini, A. Caricasole, E. Barletta, A. De Blasi, F. Nicoletti

Research output: Contribution to journalArticle

Abstract

We used cultured cerebellar granule cells to examine whether native group-III metabotropic glutamate (mGlu) receptors are coupled to the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI-3-K) pathways. Cultured granule cells responded to the group-III mGlu receptor agonist, L-amino-2-amino-4-phosphonobutanoate (L-AP4), with an increased phosphorylation and activity of MAPKs (ERK-1 and -2) and an increased phosphorylation of the PI-3-K target, protein kinase B (PKB/AKT). These effects were attenuated by the group-III antagonists, α-methyl-serine-O-phosphate (MSOP) and (R,S)-α-cyclopropyl-4-phosphonophenylglycine (CPPG), or by pretreatment of the cultures with pertussis toxin. L-AP4 also induced the nuclear translocation of β-catenin, a downstream effector of the PI-3-K pathway. To assess the functional relevance of these mechanisms we examined the ability of L-AP4 to protect granule cells against apoptosis by trophic deprivation, induced by lowering extra-cellular K+ from 25 to 10 mM. Neuroprotection by L-AP4 was attenuated by MSOP and abrogated by the compounds PD98059 and UO126, which inhibit the MAPK pathway, or by the compound LY294002, which inhibits the PI-3-K pathway. Taken together, these results show for the first time that native group-III mGlu receptors are coupled to MAPK and PI-3-K, and that activation of both pathways is necessary for neuroprotection mediated by this particular class of receptors.

Original languageEnglish
Pages (from-to)216-223
Number of pages8
JournalJournal of Neurochemistry
Volume82
Issue number2
DOIs
Publication statusPublished - 2002

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Keywords

  • β-catenin
  • Cerebellar granule cells
  • Metabotropic glutamate receptors
  • Mitogen-activated protein kinase (MAPK)
  • PI-3-kinase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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