A Signaling Mechanism from Gαq-Protein-Coupled Metabotropic Glutamate Receptors to Gene Expression: Role of the c-Jun N-Terminal Kinase Pathway

Abstract

G␣q-protein-coupled group I metabotropic glutamate receptors (mGluRs) are densely expressed in brain neurons and are actively involved in various cellular activities. In this study, we investigated the role of group I mGluRs in regulating the c-Jun N-terminal kinase (JNK)/stress-activated protein kinase in cultured neurons. We found that selective activation of mGluR5 induced a rapid and transient phosphorylation of JNK. In a series of studies to determine the mechanisms, we found that the conventional mGluR5-associated signaling pathways (inositol-1,4,5-triphosphate-mediated Ca 2ϩ release and activation of protein kinase C) were not involved in the mGluR5 regulation. Instead, ligand stimulation of mGluR5 caused a dynamic transactivation of the epidermal growth factor (EGF) receptor, which in turn triggered a downstream signaling pathway to upregulate JNK phosphorylation. Furthermore, the mGluR5-dependent JNK activation specifically activated c-Jun, but not activating transcription factor-2 or JunD, and increased activator protein-1 (AP-1)-mediated endogenous transcriptional activity. Together, we identified a novel mGluR5-to-nucleus communication through the EGF/JNK pathway, which functions to regulate AP-1-mediated transcription.

Metabotropic Glutamate Receptor-Mediated Long-Term Depression: Molecular Mechanisms

“…However, in this study there was no change in c-Jun expression levels, indicating that posttranslational modifications rather than mRNA transcription were necessary for mediating DHPG-LTD (Li et al, 2007b). A further study supports a role of c-Jun in mGluR-LTD expression in neurons (Yang et al, 2006). Activator protein-1 mediated gene expression is facilitated by a process that involves dimerization of c-Jun and Fos (Schwarzschild et al, 1997;Yang et al, 2006).…”

“…A further study supports a role of c-Jun in mGluR-LTD expression in neurons (Yang et al, 2006). Activator protein-1 mediated gene expression is facilitated by a process that involves dimerization of c-Jun and Fos (Schwarzschild et al, 1997;Yang et al, 2006).…”

Protein kinase C-regulated cAMP response element-binding protein phosphorylation in cultured rat striatal neurons

“…The standardized procedure was employed in this study to generate a predominant GABAergic neuronal culture from E19 rat embryos [25,42]. Cells grew for 10-14 days before use.…”

Activator protein-1 responsive to the group II metabotropic glutamate receptor subtype in association with intracellular calcium in cultured rat cortical neurons

“…Selective activation of the mGluR5 isoform induces a rapid and transient phosphorylation of c-Jun N-terminal kinase, followed by the induction of c-Jun protein and subsequent increase in AP1 expression in cultured neurons (Yang et al, 2006). 1S,3R-1-Amino-cyclopentane-1,3-dicarboxylate, a non-selective agonist for mGluRs, induces a rapid and transient expression of c-fos, fosB and junB mRNA, with increasing AP1 DNA binding in primary astroglial cultures (Condorelli et al, 1993).…”