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The Journal of Neuroscience, January 18, 2006, 26(3):971-980; doi:10.1523/JNEUROSCI.4423-05.2006

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

Lu Yang,¹ Limin Mao,¹ Hai Chen,¹ Michael Catavsan,¹ Jonathan Kozinn,² Anish Arora,¹ Xianyu Liu,¹ and John Q. Wang^1,2

Departments of ¹Basic Medical Science and ²Anesthesiology, University of Missouri–Kansas City School of Medicine, Kansas City, Missouri 64108

Gq-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.

Key words: mGluR; MAPK; JNK; SAPK; Jun; MKK; AP-1; EGF; striatum; nucleus accumbens

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Received Oct 17, 2005; accepted December 1, 2005.

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