PT - JOURNAL ARTICLE AU - Limin Mao AU - John Q. Wang TI - Glutamate Cascade to cAMP Response Element-Binding Protein Phosphorylation in Cultured Striatal Neurons through Calcium-Coupled Group I Metabotropic Glutamate Receptors AID - 10.1124/mol.62.3.473 DP - 2002 Sep 01 TA - Molecular Pharmacology PG - 473--484 VI - 62 IP - 3 4099 - http://molpharm.aspetjournals.org/content/62/3/473.short 4100 - http://molpharm.aspetjournals.org/content/62/3/473.full SO - Mol Pharmacol2002 Sep 01; 62 AB - Emerging evidence indicates that group I metabotropic glutamate receptors (mGluRs) play a significant role in the addictive plasticity of striatal neurons. The plasticity is probably mediated by altered cellular gene expression in relation to stimulation of group I mGluRs and associative signaling proteins. In this study, we investigated the signaling linkage of surface group I mGluRs to the nuclear transcription factor cAMP response element-binding protein (CREB) in cultured primary striatal neurons. We found that selective activation of group I mGluRs (primarily the mGluR5 subtype) was able to up-regulate CREB phosphorylation in neurochemically identified γ-aminobutyratergic neurons but not glia. The CREB phosphorylation was independent of kainate/AMPA receptors but partially dependent of concomitant NMDA receptor activation. Because L-type voltage-operated Ca2+ channel inhibitors substantially blocked the CREB phosphorylation, group I receptors are believed to lead to activation of L-type Ca2+ channels, resulting in the CREB phosphorylation. Indeed, further studies on signaling pathways showed that group I mGluRs, by activating phospholipase C, induced a rapid and transient Ca2+ release from the 1,4,5-triphosphate-sensitive rather than ryanodine-sensitive Ca2+ store. The transient Ca2+ rise in turn triggered the opening of L-type Ca2+ channels, resulting in a progressively larger increase in cytoplasmic Ca2+ levels that is responsible for subsequent CREB phosphorylation. These results indicate that Ca2+-coupled group I mGluRs possess the ability to up-regulate CREB phosphorylation via the intracellular Ca2+ release-induced activation of L-type Ca2+channels and, to a lesser extent, NMDA receptors in primary striatal neurons.