Striatal gene expression of RGS2 and RGS4 is specifically mediated by dopamine D1 and D2 receptors: clues for RGS2 and RGS4 functions.
Of all partners involved in G-protein coupled receptor (GPCR) signalling, the regulator of G-protein signalling (RGS) proteins are the only ones showing fast gene expression changes after various stimuli. These expression changes can offer feedback regulation to GPCR signalling as RGS accelerate the return of G-proteins to their inactive form and exert regulatory functions on intracellular effectors. However, it is not yet known which RGS regulate which receptor transduction pathways in the brain. To start to answer this question, we studied the influence of specific agonists and antagonists of the dopamine D1 and D2 receptors on the gene expression of the five most abundant RGS in the striatum: RGS2, RGS4, RGS8, RGS9 and RGS10. Only changes in RGS2 and RGS4 mRNA levels were observed. The D1 agonist SKF82958 and D2 antagonist haloperidol caused an up-regulation of RGS2 (+ 38.0% and + 41.6%, respectively). The D1 antagonist SCH23390 and D2 agonist quinpirole caused a down-regulation of RGS2 (- 25.0% and - 35.0%) and an up-regulation of RGS4 (+ 57.2% and + 52.5%). D1 and D2 receptors exert opposite effects on RGS2 expression, as they do on cAMP levels, suggesting a cAMP-mediated transcription of RGS2. This was confirmed by the unique induction of RGS2 (+ 111.1%) observed in the periventricular zone of the striatum after intracerebroventricular injection of forskolin. RGS4 was up-regulated only when RGS2 was down-regulated. This suggests that both RGS exert distinct functions. Considering the coupling of D1 and D2 receptors to the intracellular effector adenylate cyclase 5 (AC5) through their respective Galpha subunits in the striatum, our data allow us to suggest that RGS2 regulates the D1/Galphaolf/AC5 pathway and RGS4 the D2/Galphao/AC5 pathway.
Taymans
Jean-Marc
JM
Central Nervous System Discovery Research, Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
Leysen
Josée E
JE
Langlois
Xavier
X
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D005576:Colforsin / Q000008:administration & dosage; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D017403:In Situ Hybridization; D007276:Injections, Intraventricular; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D020710:RGS Proteins; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C491068:Rgs10 protein, mouse; C491067:Rgs10 protein, rat; C105345:Rgs2 protein, mouse; C486485:Rgs8 protein, rat; C116925:regulator of g-protein signaling 9; C098799:RGS4 protein; D005576:Colforsin; D000661:Amphetamine