Disease relevance of Rgs4

• We find that RGS3 and RGS4 are constitutively expressed at high levels in C-fiber primary sensory neurons in the adult rat dorsal root ganglion (DRG) and transection of the sciatic nerve results in a substantial down regulation of these transcripts [1].
• These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease [2].
• The up-regulation of RGS4 mRNA was significantly blocked by co-treatment with respective opioid antagonists (mu: naloxone, kappa: norbinaltorphimine) or pretreatment with pertussis toxin [3].
• In present studies, a replication-deficient herpes simplex virus (HSV) was used to elevate RGS4 mRNA in the rat dorsal raphe nuclei (DRN) while extracellular levels of 5-HT in the striatum were monitored by in vivo microdialysis [4].

High impact information on Rgs4

• Structure of RGS4 bound to AlF4--activated G(i alpha1): stabilization of the transition state for GTP hydrolysis [5].
• The binding site for RGS4 on G(i alpha1) is also consistent with the activity of RGS proteins as antagonists of G(alpha) effectors [5].
• This adaptation was attributable to the upregulation of RGS4-an autoreceptor-associated, GTPase-accelerating protein [2].
• RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion [2].
• We found that phenylephrine-mediated and endothelin-1-mediated induction of the atrial natriuretic factor and myosin light chain-2 genes was inhibited in cells that were transfected with RGS4 [6].

Biological context of Rgs4

• High basal expression and injury-induced down regulation of two regulator of G-protein signaling transcripts, RGS3 and RGS4 in primary sensory neurons [1].
• 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) [7].
• Conversely, RGS4 gene expression is independent of presynaptic D2 receptors [7].
• Alterations in RGS protein levels, in particular RGS2 and RGS4, produce cardiovascular phenotypes [8].
• Phenylephrine-mediated myofilament organization and cell growth were also blocked in cells by RGS4 [6].

Anatomical context of Rgs4

• RGS4 mRNA is notable for its dense expression in neocortex, piriform cortex, caudoputamen, and ventrobasal thalamus [9].
• The increased RGS4 mRNA levels in hypothalamus were significant by 2 h following an acute ECS [10].
• In the neocortex, RGS2 mRNA was enriched in the superficial cortical plate at P2, in contrast to RGS4, which was enriched in more mature neurons of the deeper layer V and VI [11].
• The peaks of RGS4 expression were seen in the following regions with distinct onset and duration: the neocortex (from P2 onward), the hippocampus (P10 and P18) and the thalamus (from P18 onward) [11].
• RGS4 expression was temporarily confined to the CA pyramidal cell layer and not detectable in the dentate gyrus at P10 and P18 [11].

Associations of Rgs4 with chemical compounds

• 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 [7].
• The expression of the G-protein regulatory factors RGS2 and RGS4 were increased by nearly 3-fold by phenylephrine treatment although this was completely prevented by adenosine receptor agonists [12].
• Treatment of the PC12 cells with forskolin, dibutryl cAMP, or 8-CPT-cAMP for three hours decreased RGS4 message by nearly 50% [13].
• Opposite results were obtained concerning the regulation of RGS4 since L-dopa alone was without effect whereas co-administration of L-dopa and R(+)-SCH23390 significantly enhanced the RGS4 mRNA levels (by 38%) [14].
• Actinomycin D, a potent inhibitor of transcription, did not affect the forskolin-induced decrease in RGS4 message, suggesting that forskolin does not alter RGS4 message half-life [13].

Regulatory relationships of Rgs4

• RGS4 was up-regulated only when RGS2 was down-regulated [15].

Other interactions of Rgs4

• 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%) [15].
• In ventromedial hypothalamus, RGS4 mRNA content was increased 24 h following chronic ECS, whereas RGS7 mRNA levels were only increased 24 h following an acute ECS [10].
• At 24 h following a chronic ECS regimen, RGS4, -7, and -10 mRNA levels were reduced by 20-30%; only RGS10 was significantly reduced 24 h after acute ECS [10].
• The level of RGS 9 mRNA, which shows strong striatal-specific expression, steadily decreased over a 4-h interval, whereas RGS 4 and 16 and the 3.9-kb transcript of RGS 8 were not significantly affected at any point examined [16].

Analytical, diagnostic and therapeutic context of Rgs4

• The results clearly show a selective increase in the mRNA levels of RGS2, 5 and 8 and a decrease in RGS4 and 9 mRNA levels following nigrostriatal denervation [17].
• Moreover, the 5-HT(1A) regulation of NMDA receptors was significantly enhanced in a subset of PFC pyramidal neurons from rats treated with subchronic phencyclidine, an animal model of schizophrenia, which was found to be associated with specifically decreased RGS4 expression in these cells [18].
• In this study, by northern blotting analysis, we investigated the regulation of RGS4 mRNA by opioid receptor agonists in PC12 cells stably expressing either cloned mu- or kappa-opioid receptors [3].

References