F. Ferraguti et al., Activation of the extracellular signal-regulated kinase 2 by metabotropic glutamate receptors, EUR J NEURO, 11(6), 1999, pp. 2073-2082
Activation of metabotropic glutamate receptors (mGluRs) leads to modulation
of a variety of second messenger pathways probably including the mitogen-a
ctivated protein kinase (MAPK) extracellular signal-regulated protein kinas
es (ERK). MAPK play a key role in the control of cellular responses to chan
ges in the external environment by regulating transcriptional activity and
the phosphorylation state of several cytoplasmic targets. In this study, Ch
inese hamster ovary (CHO) cells permanently transfected with rat mGluR1a, m
GluR2 and mGluR4 were employed as a model to examine the activation of MAPK
by glutamate through mGluRs. Ail three mGluR subtypes rapidly stimulated E
RK activation. In particular, mGluR1a and mGluR2 preferentially mediated ph
osphorylation and activation of ERK2 in a pertussis toxin (PTX)-sensitive a
nd concentration-dependent manner. The activation was blocked completely by
pretreatment with the antagonist (Rs)-alpha-methyl-4-carboxyphenylglycine
(MCPG) or with the MEK inhibitor PD098059. Furthermore, mGluR1a-mediated ER
K activation was suppressed by the depletion of endogenous protein kinase C
(PKC) activity and by the PKC inhibitors staurosporine and calphostin C, b
ut not chelerythrine. When cAMP was elevated in mGluR2-expressing cells, by
forskolin or dibutyryl-cAMP, slight elevation of ERK activity was observed
. However, glutamate-stimulated ERK activation remained unaffected. In thes
e cells, the phosphatidylinositol 3 kinase (PI3K) inhibitor wortmannin prod
uced a significant, albeit only partial, inhibition of mGluR2-mediated ERK
activation. These findings raise the possibility of a MAPK cascade involvem
ent in glutamate-dependent neuronal plasticity mediated through stimulation
of mGluRs.