Induction of c-fos and zif/268 gene expression in rat striatal neurons, following stimulation of D1-like dopamine receptors, involves protein kinase A and protein kinase C.
Changes in the level of dopaminergic activity in the rat striatum lead to the induction of a number of immediate-early genes, including c-fos and zif/268. These immediate-early genes are thought in turn to alter the rate of transcription of downstream genes. There is evidence that the dopaminergic activation of the c-fos and zif/268 genes in the striatum in vivo is linked to stimulation of D1-like dopamine receptors. We have used primary cultures of embryonic rat striatal neurons to identify the intracellular pathways involved in this response. Dopamine (10 nM-5 microM) caused a marked increase in the levels of c-fos mRNA and zif/268 mRNA in cultured striatal neurons, an effect that was reproduced by the D1-like dopamine receptor agonist SKF38393 (10 nM-5 microM). These actions were attenuated by the D1-like antagonist SCH23390 (1 microM) but not by the D2-like antagonist eticlopride (1 microM). The D2-like agonist quinpirole did not increase zif/268 mRNA above basal levels at concentrations up to 5 microM, but caused a slight increase in the levels of c-fos mRNA. The stimulation of c-fos mRNA levels caused by 1 microM SKF38393 was reduced by 45% following pretreatment with the selective protein kinase A inhibitor KT5720, and by 87% following pretreatment with the selective protein kinase C inhibitor calphostin C. The stimulation of zif/268 mRNA levels caused by 1 microM SKF38393 was reduced by 90% following pretreatment with KT5720, but was not significantly affected by pretreatment with calphostin C. In addition, the actions of SKF38393 to stimulate the expression of both immediate-early genes were attenuated by coadministration of quinpirole. These results suggest that SKF38393 acts on striatal neurons to stimulate c-fos expression predominantly through protein kinase C, but also partially through protein kinase A. Conversely, SKF38393 induces zif/268 expression through protein kinase A. The ability of quinpirole to antagonize the actions of SKF38393 on cultured neurons is consistent with the presence of both D1-like receptors on the same neuronal population.
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D018491:Dopamine Agonists / Q000494:pharmacology*; D051766:Early Growth Response Protein 1; D004873:Ergolines / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000187:drug effects*; D016762:Genes, fos / Q000235:genetics; D017874:Immediate-Early Proteins; D017403:In Situ Hybridization; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D009434:Neural Pathways / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000378:metabolism; D015345:Oligonucleotide Probes; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019257:Quinpirole; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000819:agonists*; D015290:Second Messenger Systems / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
D004268:DNA-Binding Proteins; D018491:Dopamine Agonists; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D004873:Ergolines; D017874:Immediate-Early Proteins; D015345:Oligonucleotide Probes; D017447:Receptors, Dopamine D1; D014157:Transcription Factors; D019257:Quinpirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C