Glutamate, But Not Dopamine, Stimulates Stress-Activated Protein Kinase and AP-1-Mediated Transcription in Striatal Neurons

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Abstract
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-fosmRNA 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.