Dopaminergic regulation of AP-1 transcription factor DNA binding activity in rat striatum.
Dopaminergic modulation of the DNA binding activity of AP-1, Sp1, CREB and AP-2 transcription factors was examined in rat striatal nuclear extracts by gel shift assay. AP-1 binding was selectively increased in the striatum following depletion of dopamine by 6-hydroxydopamine-induced lesion of the nigrostriatal pathway or after reserpine treatment. The D1 agonist SKF 38393 dose-dependently increased AP-1 binding; this effect was significantly increased in reserpine-treated rats and even more markedly enhanced in denervated striatum. The D2/D3 agonist quinpirole, administered alone, did not affect striatal activator protein-1 binding; in combination, quinpirole and SKF 38393 acted synergistically in normal and reserpine-treated rats but not in 6-hydroxydopamine-lesioned rats, suggesting that mechanisms underlying D1-D2/D3 interactions are altered after dopamine denervation. Most, but not all, of the changes in AP-1 binding activity observed in this study are consistent with changes in levels of Fos/Jun family proteins observed after similar treatments. These results support the hypothesis that D1 receptor stimulation activates striatonigral neurons and modulates expression of AP-1-related genes in these neurons, while D2 receptor stimulation mediates tonic inhibition of AP-1 expression and activity in the striatopallidal neurons. Moreover, the findings provide evidence that the loss of dopaminergic input to the striatum, as occurs in Parkinson's disease, induces long-lasting alterations in the regulation of striatal gene expression which may contribute to the disease's progress.
Huang
K X
KX
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1406, USA.
Walters
J R
JR
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism*; D004247:DNA / Q000187:drug effects*; D004298:Dopamine / Q000502:physiology*; D008297:Male; D016627:Oxidopamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014157:Transcription Factors / Q000502:physiology*
D018808:Transcription Factor AP-1; D014157:Transcription Factors; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; D004247:DNA; D004298:Dopamine