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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Phosphatidylinositol 3-Kinase
Metabotropic Glutamate Receptors
Mitogen-Activated Protein Kinases
Phosphoserine
Phosphorylation
Serine
Phosphates
Excitatory Amino Acid Agonists
Catenins
Proto-Oncogene Proteins c-akt
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Pertussis Toxin
Cultured Cells
Chemical activation
Apoptosis
2-amino-4-phosphono-propinate

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

Cite this

Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways. / Iacovelli, L.; Bruno, V.; Salvatore, L.; Melchiorri, D.; Gradini, R.; Caricasole, A.; Barletta, E.; De Blasi, A.; Nicoletti, F.

In: Journal of Neurochemistry, Vol. 82, No. 2, 2002, p. 216-223.

Research output: Contribution to journalArticle

Iacovelli, L. ; Bruno, V. ; Salvatore, L. ; Melchiorri, D. ; Gradini, R. ; Caricasole, A. ; Barletta, E. ; De Blasi, A. ; Nicoletti, F. / Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways. In: Journal of Neurochemistry. 2002 ; Vol. 82, No. 2. pp. 216-223.
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T1 - Native group-III metabotropic glutamate receptors are coupled to the mitogen-activated protein kinase/phosphatidylinositol-3-kinase pathways

AU - Iacovelli, L.

AU - Bruno, V.

AU - Salvatore, L.

AU - Melchiorri, D.

AU - Gradini, R.

AU - Caricasole, A.

AU - Barletta, E.

AU - De Blasi, A.

AU - Nicoletti, F.

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N2 - 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.

AB - 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.

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