Glutamate, but not dopamine, stimulates stress-activated protein kinase and AP-1-mediated transcription in striatal neurons.
Drugs that stimulate dopamine and glutamate receptors have been shown to induce the expression of AP-1 proteins (such as c-Fos and c-Jun) in the striatum and to induce binding of these proteins to AP-1 sites on DNA, leading to the hypothesis that AP-1-mediated transcription contributes to the long-term effects of these drugs. To examine this hypothesis, we compared the regulation of AP-1-mediated transcription to the inductions of AP-1-binding activity and genes encoding AP-1 proteins in primary cultures of striatal neurons. Although glutamate, dopamine, and forskolin (an activator of adenylate cyclase) all induce c-fos mRNA and AP-1 binding, we found, surprisingly, that only glutamate induces transcription of a transfected AP-1-driven fusion gene. To explore the basis for this discrepancy, we investigated the possibility that the phosphorylation of c-Jun may also be required for AP-1-mediated transcription in striatal neurons. Glutamate, but neither dopamine nor forskolin, raises the levels of phosphorylated c-Jun as well as the activity of a Jun kinase (SAPK/JNK) in striatal cultures. Both the glutamatergic induction of AP-1-mediated transcription and activation of SAPK/JNK appear to be mediated, at least in part, via NMDA receptors. In striatal neurons, the phosphorylation of AP-1 proteins produced by glutamate may be required to convert AP-1 protein expression and binding to transcriptional activation.
Schwarzschild
M A
MA
Laboratory of Molecular and Developmental Neuroscience, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Cole
R L
RL
Hyman
S E
SE
D051698:Activating Transcription Factor 2; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D005576:Colforsin / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases; D016350:Leucine Zippers / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases; D017072:Neostriatum / Q000166:cytology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D051698:Activating Transcription Factor 2; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D005576:Colforsin; D018698:Glutamic Acid; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D004298:Dopamine