Glutamate cascade to cAMP response element-binding protein phosphorylation in cultured striatal neurons through calcium-coupled group I metabotropic glutamate receptors.
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 gamma-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 Ca(2+) channel inhibitors substantially blocked the CREB phosphorylation, group I receptors are believed to lead to activation of L-type Ca(2+) 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 Ca(2+) release from the 1,4,5-triphosphate-sensitive rather than ryanodine-sensitive Ca(2+) store. The transient Ca(2+) rise in turn triggered the opening of L-type Ca(2+) channels, resulting in a progressively larger increase in cytoplasmic Ca(2+) levels that is responsible for subsequent CREB phosphorylation. These results indicate that Ca(2+)-coupled group I mGluRs possess the ability to up-regulate CREB phosphorylation via the intracellular Ca(2+) release-induced activation of L-type Ca(2+) channels and, to a lesser extent, NMDA receptors in primary striatal neurons.
Mao
Limin
L
Department of Pharmacology, School of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri 64108, USA.
Wang
John Q
JQ
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
D001578:Benzopyrans; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D017362:Cyclic AMP Response Element-Binding Protein; C442478:N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D018698:Glutamic Acid; D008734:Methoxyhydroxyphenylglycol; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D010738:Type C Phospholipases; D007608:Kainic Acid; D002118:Calcium; C010117:3,4-dihydroxyphenylglycol