Extracellular signal-regulated kinases (ERK) and protein kinase C (PKC) activities are involved in the modulation of Nur77 and Nor-1 expression by dopaminergic drugs.
The dopamine system is the main target of antipsychotic and psychostimulant drugs. These drugs induce intracellular events that culminate in the transcription of immediate early genes, such as c-fos. Another class of transcription factors, namely, the nuclear receptor subgroup called Nurs (Nur77, Nurr1 and Nor-1), has recently been associated with behavioral and biochemical effects mediated by dopamine. However, the signaling cascade leading to modulation of Nur mRNA levels in the brain has never been investigated. In the present study, we explore in vivo using specific kinase inhibitors the role of mitogen-associated and extracellular signal-regulated kinases (MEK) and protein kinase C (PKC) in the modulation of Nur expression induced by dopamine receptor drugs. Modulation of Nur77 expression by a dopamine D(2) receptor antagonist is associated with MEK and PKC activities, whereas only the PKC activity participates in the modulation of Nor-1 expression. Both MEK and PKC activities also participate in the modulation of Nur77 mRNA levels induced by dopamine receptor agonists, whereas a selective MEK activity is associated with the modulation of Nor-1 mRNA levels. Interestingly, modulation of dopamine drug-induced locomotor activities by kinase inhibitors is in accordance with the effects on Nur77, but not Nor-1, expression. Taken together, the results indicate that signaling events leading to modulation of Nur77 and Nor-1 expression following dopamine receptor interacting drugs are distinct. Considering that orphan nuclear receptors of the Nur subgroup display an important ligand-independent constitutive activity, characterization of the signaling cascades involved in the regulation of their expression represents an important step for understanding their role in dopamine system physiology and pathophysiology.
Bourhis
Emmanuelle
E
Faculté de Pharmacie, Université de Montréal, Montréal, Quebec, Canada.
Maheux
Jérôme
J
Rouillard
Claude
C
Lévesque
Daniel
D
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced / Q000503:physiopathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011493:Protein Kinase C / Q000378:metabolism*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D015259:Dopamine Agents; D004791:Enzyme Inhibitors; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases