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

• DOI: 10.1046/j.1471-4159.2002.00929.x
• Publication Date: 2003-03-12T07:01:39Z
• Authors: L. Iacovelli; V. Bruno; L. Salvatore; D. Melchiorri; R. Gradini; A. Caricasole; E. Barletta; A. De Blasi; F. Nicoletti
• Keywords: Neurons; 0303 health sciences; MAP Kinase Signaling System; Aminobutyrates; Active Transport, Cell Nucleus; Apoptosis; beta-catenin; cerebellar granule cells; metabotropic glutamate receptors; mglu; mitogen-activated protein kinase (mapk); pi-3-kinase; protein kinase/phosphatidylinositol-3-kinase; β-catenin; Protein Serine-Threonine Kinases; Enzyme Activation; Cytoskeletal Proteins; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Neuroprotective Agents; Excitatory Amino Acid Agonists; Potassium; Animals; Enzyme Inhibitors; Mitogen-Activated Protein Kinases; Phosphorylation; Excitatory Amino Acid Antagonists; Cell Division; Cells, Cultured; Phosphoinositide-3 Kinase Inhibitors

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