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

• DOI: 10.1523/jneurosci.4423-05.2006
• Publication Date: 2006-01-18T20:03:05Z
• Authors: Lu Yang; Limin Mao; Hai Chen; Michael Catavsan; Jonathan Kozinn; Anish Arora; Xianyu Liu; John Q. Wang
• Keywords: 0303 health sciences; Dose-Response Relationship, Drug; Receptor, Metabotropic Glutamate 5; JNK Mitogen-Activated Protein Kinases; Glutamic Acid; Receptors, Metabotropic Glutamate; Methoxyhydroxyphenylglycol; Rats; 03 medical and health sciences; Gene Expression Regulation; Animals; GTP-Binding Protein alpha Subunits, Gq-G11; Phosphorylation; Cells, Cultured; Signal Transduction

Gαq-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 Ca2+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.