Taymans Jean-Marc, Leysen Josée E, Langlois Xavier
Central Nervous System Discovery Research, Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, B-2340 Beerse, Belgium.
J Neurochem. 2003 Mar;84(5):1118-27. doi: 10.1046/j.1471-4159.2003.01610.x.
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.
在参与G蛋白偶联受体（GPCR）信号传导的所有伙伴中，G蛋白信号调节（RGS）蛋白是唯一在各种刺激后显示快速基因表达变化的蛋白。这些表达变化可为GPCR信号传导提供反馈调节，因为RGS加速G蛋白返回其无活性形式并对细胞内效应器发挥调节功能。然而，尚不清楚哪些RGS调节大脑中的哪些受体转导途径。为了开始回答这个问题，我们研究了多巴胺D1和D2受体的特异性激动剂和拮抗剂对纹状体中五种最丰富的RGS（RGS2、RGS4、RGS8、RGS9和RGS10）基因表达的影响。仅观察到RGS2和RGS4 mRNA水平的变化。D1激动剂SKF82958和D2拮抗剂氟哌啶醇导致RGS2上调（分别为+38.0%和+41.6%）。D1拮抗剂SCH23390和D2激动剂喹吡罗导致RGS2下调（-25.0%和-35.0%）和RGS4上调（+57.2%和+52.5%）。D1和D2受体对RGS2表达的影响与它们对cAMP水平的影响相反，这表明RGS2是由cAMP介导转录的。脑室内注射福斯高林后，在纹状体室周区观察到RGS2独特的诱导上调（+111.1%），这证实了上述结论。只有当RGS2下调时，RGS4才会上调。这表明这两种RGS发挥着不同的功能。考虑到D1和D2受体通过它们在纹状体中各自的Gα亚基与细胞内效应器腺苷酸环化酶5（AC5）偶联，我们的数据使我们能够推测RGS2调节D1/Gαolf/AC5途径，而RGS4调节D2/Gαo/AC5途径。
