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Rgs4  -  regulator of G-protein signaling 4

Rattus norvegicus

Synonyms: RGP4, RGS4, Regulator of G-protein signaling 4
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Disease relevance of Rgs4


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


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].


  1. High basal expression and injury-induced down regulation of two regulator of G-protein signaling transcripts, RGS3 and RGS4 in primary sensory neurons. Costigan, M., Samad, T.A., Allchorne, A., Lanoue, C., Tate, S., Woolf, C.J. Mol. Cell. Neurosci. (2003) [Pubmed]
  2. RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion. Ding, J., Guzman, J.N., Tkatch, T., Chen, S., Goldberg, J.A., Ebert, P.J., Levitt, P., Wilson, C.J., Hamm, H.E., Surmeier, D.J. Nat. Neurosci. (2006) [Pubmed]
  3. Up-regulation of RGS4 mRNA by opioid receptor agonists in PC12 cells expressing cloned mu- or kappa-opioid receptors. Nakagawa, T., Minami, M., Satoh, M. Eur. J. Pharmacol. (2001) [Pubmed]
  4. Regulators of G-protein signaling 4: modulation of 5-HT1A-mediated neurotransmitter release in vivo. Beyer, C.E., Ghavami, A., Lin, Q., Sung, A., Rhodes, K.J., Dawson, L.A., Schechter, L.E., Young, K.H. Brain Res. (2004) [Pubmed]
  5. Structure of RGS4 bound to AlF4--activated G(i alpha1): stabilization of the transition state for GTP hydrolysis. Tesmer, J.J., Berman, D.M., Gilman, A.G., Sprang, S.R. Cell (1997) [Pubmed]
  6. RGS4 inhibits G-protein signaling in cardiomyocytes. Tamirisa, P., Blumer, K.J., Muslin, A.J. Circulation (1999) [Pubmed]
  7. Dopamine receptor-mediated regulation of RGS2 and RGS4 mRNA differentially depends on ascending dopamine projections and time. Taymans, J.M., Kia, H.K., Claes, R., Cruz, C., Leysen, J., Langlois, X. Eur. J. Neurosci. (2004) [Pubmed]
  8. Multi-tasking RGS proteins in the heart: the next therapeutic target? Riddle, E.L., Schwartzman, R.A., Bond, M., Insel, P.A. Circ. Res. (2005) [Pubmed]
  9. Regulators of G-protein signaling (RGS) proteins: region-specific expression of nine subtypes in rat brain. Gold, S.J., Ni, Y.G., Dohlman, H.G., Nestler, E.J. J. Neurosci. (1997) [Pubmed]
  10. Regulation of regulators of G protein signaling mRNA expression in rat brain by acute and chronic electroconvulsive seizures. Gold, S.J., Heifets, B.D., Pudiak, C.M., Potts, B.W., Nestler, E.J. J. Neurochem. (2002) [Pubmed]
  11. Expression of RGS2, RGS4 and RGS7 in the developing postnatal brain. Ingi, T., Aoki, Y. Eur. J. Neurosci. (2002) [Pubmed]
  12. Inhibition of phenylephrine-induced cardiomyocyte hypertrophy by activation of multiple adenosine receptor subtypes. Gan, X.T., Rajapurohitam, V., Haist, J.V., Chidiac, P., Cook, M.A., Karmazyn, M. J. Pharmacol. Exp. Ther. (2005) [Pubmed]
  13. Regulation of RGS mRNAs by cAMP in PC12 cells. Pepperl, D.J., Shah-Basu, S., VanLeeuwen, D., Granneman, J.G., MacKenzie, R.G. Biochem. Biophys. Res. Commun. (1998) [Pubmed]
  14. Opposite modulation of regulators of G protein signalling-2 RGS2 and RGS4 expression by dopamine receptors in the rat striatum. Geurts, M., Hermans, E., Maloteaux, J.M. Neurosci. Lett. (2002) [Pubmed]
  15. Striatal gene expression of RGS2 and RGS4 is specifically mediated by dopamine D1 and D2 receptors: clues for RGS2 and RGS4 functions. Taymans, J.M., Leysen, J.E., Langlois, X. J. Neurochem. (2003) [Pubmed]
  16. Regulators of G protein signaling: rapid changes in mRNA abundance in response to amphetamine. Burchett, S.A., Volk, M.L., Bannon, M.J., Granneman, J.G. J. Neurochem. (1998) [Pubmed]
  17. Altered expression of regulators of G-protein signaling (RGS) mRNAs in the striatum of rats undergoing dopamine depletion. Geurts, M., Maloteaux, J.M., Hermans, E. Biochem. Pharmacol. (2003) [Pubmed]
  18. RGS4 Modulates Serotonin Signaling in Prefrontal Cortex and Links to Serotonin Dysfunction in a Rat Model of Schizophrenia. Gu, Z., Jiang, Q., Yan, Z. Mol. Pharmacol. (2007) [Pubmed]
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