Activation of the extracellular signal‐regulated kinase 2 by metabotropic glutamate receptors

Abstract

Activation of metabotropic glutamate receptors (mGluRs) leads to modulation of a variety of second messenger pathways probably including the mitogen-activated protein kinase (MAPK) extracellular signal-regulated protein kinases (ERK). MAPK play a key role in the control of cellular responses to changes in the external environment by regulating transcriptional activity and the phosphorylation state of several cytoplasmic targets. In this study, Chinese hamster ovary (CHO) cells permanently transfected with rat mGluR1a, mGluR2 and mGluR4 were employed as a model to examine the activation of MAPK by glutamate through mGluRs. All three mGluR subtypes rapidly stimulated ERK activation. In particular, mGluR1a and mGluR2 preferentially mediated phosphorylation and activation of ERK2 in a pertussis toxin (PTX)-sensitive and 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 ERK activation was suppressed by the depletion of endogenous protein kinase C (PKC) activity and by the PKC inhibitors staurosporine and calphostin C, but 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 these cells, the phosphatidylinositol 3 kinase (PI3K) inhibitor wortmannin produced a significant, albeit only partial, inhibition of mGluR2-mediated ERK activation. These findings raise the possibility of a MAPK cascade involvement in glutamate-dependent neuronal plasticity mediated through stimulation of mGluRs.

Metabotropic Glutamate Receptors and Dopamine Receptors Cooperate to Enhance Extracellular Signal-Regulated Kinase Phosphorylation in Striatal Neurons

“…The availability of highly specific antibodies to phosphorylated ERK1/2 facilitated this analysis. Ras pathway activation leading to increased ERK2 phosphorylation has been characterized as a cellular event resulting from mGluR5 activation (Fiore et al, 1993;Ferraguti et al, 1999). We observed rapid increases in pERK2 with low concentrations of DHPG mediated primarily by mGluR5, the contribution from mGluR1 being much less apparent.…”

Amphetamine Increases Phosphorylation of Extracellular Signal-regulated Kinase and Transcription Factors in the Rat Striatum via Group I Metabotropic Glutamate Receptors

“…Similarly, mGluR1a mediates phosphorylation of ERK2 in Chinese hamster ovary cells transfected with rat mGluRs (Ferraguti et al 1999) and rat cortical cultures (Fiore et al 1993). ERK1/2 has been found to be a major kinase phosphorylating CREB and Elk-1.…”

BDNF Protects the Neonatal Brain from Hypoxic-Ischemic InjuryIn Vivovia the ERK Pathway

“…In light of this, it is interesting to note that stimulation of neurotransmitter receptors such as muscarinic acetylcholine receptors results in prolonged activation of ERK1/2 both in vitro and in vivo (Rosenblum et al, 2000). A variety of agents such as ligands for specific neurotransmitter receptors (Ferraguti et al, 1999;Hayashi et al, 1999;Mukherjee et al, 1999;Yan et al, 1999), nitric oxide (Yun et al, 1998), and estrogen (Singh et al, 1999) can activate the neuronal ERK pathway in vitro. A search for agents that can activate the ERK pathway or its downstream mediators in neurons in vivo seems warranted to attempt to develop better therapies against neonatal H-I brain injury.…”