Dopamine receptor-mediated regulation of RGS2 and RGS4 mRNA differentially depends on ascending dopamine projections and time.
RGS2 and RGS4 mRNAs are regulated in the rat striatum by dopaminergic agents. The present study further characterizes this regulation in three experiments. First, dopamine type 1 (receptor) (D1)- and dopamine type 2 (receptor) (D2)-mediated regulator of G-protein signalling (RGS) gene regulation was investigated in animals with deleted ascending dopaminergic pathways. We showed that RGS2 expression is controlled by D1 receptors either by direct action on D1 receptors or indirectly by presynaptic D2 receptors. Conversely, RGS4 gene expression is independent of presynaptic D2 receptors. Second, the study of colocalization between RGS2 or RGS4 and D1 or D2 by double labelling in situ hybridization histochemistry revealed broad expression of RGS2 and RGS4 mRNA in striatal subpopulations with colocalization of RGS2 and RGS4 with both D1 and D2 receptors. Finally, to test how far their gene regulation is temporally concerted, changes in RGS2 and RGS4 mRNA levels were measured in parallel with receptor occupancy by specific dopaminergic drugs at different time-points. RGS2 was rapidly/transiently up-regulated by the D1 agonist SKF82958 and the D2 antagonist haloperidol (peak at 0.5 h) and down-regulated by the D1 antagonist SCH23390 and the D2 agonist quinpirole (trough at 1 and 2 h). RGS4 showed a delayed/transient up-regulation with SCH23390 and quinpirole (peak at 4 and 2 h) and down-regulation with haloperidol (trough at 8 h). Depending on the drug used, the degree of receptor occupancy did (D1 agonist and RGS2) or did not (D2 antagonist and RGS2) run parallel to RGS gene expression changes, indicating that certain drug effects are direct and others indirect. The precise control of RGS2 and RGS4 expression by dopamine receptors pleads in favour of their potential contribution to the fine-tuning of D1 and D2 receptor signalling cascades.
Taymans
Jean-Marc
JM
Johnson and Johnson Pharmaceutical Research and Development, Central Nervous System Discovery Research, Psychiatry One Department, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Kia
Hossein Kami
HK
Claes
Robby
R
Cruz
Catarina
C
Leysen
Josée
J
Langlois
Xavier
X
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D008297:Male; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D020710:RGS Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D011954:Receptors, Dopamine / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D020710:RGS Proteins; D012333:RNA, Messenger; D011954:Receptors, Dopamine; C105345:Rgs2 protein, mouse; C098799:RGS4 protein; D004298:Dopamine