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 contr ibutes to the long-term effects of these drugs. To examine this hypoth esis, 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 mR NA and AP-1 binding, we found, surprisingly, that only glutamate induc es transcription of a transfected AP-1-driven fusion gene. To explore the basis for this discrepancy, we investigated the possibility that t he phosphorylation of c-Jun may also be required for AP-1-mediated tra nscription in striatal neurons. Glutamate, but neither dopamine nor fo rskolin, raises the levels of phosphorylated c-Jun as well as the acti vity of a Jun kinase (SAPK/JNK) in striatal cultures. Both the glutama tergic induction of AP-1-mediated transcription and activation of SAPK /JNK appear to be mediated, at least in part, via NMDA receptors. In s triatal neurons, the phosphorylation of AP-1 proteins produced by glut amate may be required to convert AP-1 protein expression and binding t o transcriptional activation.