title: Interactions between ionotropic and metabotropic glutamate receptors regulate cAMP response element-binding protein phosphorylation in cultured striatal neurons.
abstract: The striatum is a key structure of basal ganglia controlling extrapyramidal motor activity and processing addictive plasticity of abused substances. Glutamatergic transmission that is enriched in the striatum regulates a variety of striatal neuronal activities via selective activation of ionotropic and metabotropic glutamate receptors (mGluRs). In this study, the interaction between N-methyl-D-aspartate (NMDA) receptors and group I mGluRs (mGluR1 and mGluR5 subtypes) in activating a phosphorylation cascade to a transcription factor cAMP response element-binding protein (CREB) was investigated in primary cultures of E18 or postnatal day 1 striatal neurons. We found that activation of NMDA receptors with NMDA rapidly and concentration-dependently increased the number of neurons expressing phosphorylated CREB (pCREB) as revealed by immunocytochemistry. The increased pCREB expression by NMDA was sensitive to an NMDA antagonist MK801. Co-incubation of a subthreshold dose of a group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) that itself did not alter basal pCREB expression augmented NMDA-induced CREB phosphorylation. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride blocked the DHPG augmentation of NMDA-induced CREB phosphorylation, while the mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester did not. Interestingly, the protein kinase C inhibitors chelerythrine and Gö6983 also prevented DHPG from enhancing CREB phosphorylation induced by NMDA. Whereas a low dose of the protein kinase C activator phorbol 12-myristate 13-acetate mimicked the DHPG potentiation. These results indicate a facilitatory regulation of an NMDA cascade to CREB phosphorylation by concurrent glutamatergic tone on mGluR5, which is probably processed via an intracellular signaling pathway involving protein kinase C.
authors.affiliation: Department of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, 2411 Holmes Street, Room M3-C225, 64108, USA.
authors.forename: L
authors.initials: L
authors.lastname: Mao
authors.forename: J Q
authors.initials: JQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D002118:Calcium; D002273:Carcinogens; D017362:Cyclic AMP Response Element-Binding Protein; D018690:Excitatory Amino Acid Agonists; D008734:Methoxyhydroxyphenylglycol; D016202:N-Methylaspartate; D011493:Protein Kinase C; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D013755:Tetradecanoylphorbol Acetate; C010117:3,4-dihydroxyphenylglycol