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 language | English |
|---|---|
| Pages (from-to) | 216-223 |
| Number of pages | 8 |
| Journal | Journal of Neurochemistry |
| Volume | 82 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2002 |
Fingerprint
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 journal › Article
}
TY - JOUR
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.
PY - 2002
Y1 - 2002
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.
KW - β-catenin
KW - Cerebellar granule cells
KW - Metabotropic glutamate receptors
KW - Mitogen-activated protein kinase (MAPK)
KW - PI-3-kinase
UR - http://www.scopus.com/inward/record.url?scp=0036068715&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0036068715&partnerID=8YFLogxK
U2 - 10.1046/j.1471-4159.2002.00929.x
DO - 10.1046/j.1471-4159.2002.00929.x
M3 - Article
C2 - 12124422
AN - SCOPUS:0036068715
VL - 82
SP - 216
EP - 223
JO - Journal of Neurochemistry
JF - Journal of Neurochemistry
SN - 0022-3042
IS - 2
ER -