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Gene Review

RGS4  -  regulator of G-protein signaling 4

Homo sapiens

Synonyms: RGP4, Regulator of G-protein signaling 4, SCZD9
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Disease relevance of RGS4

  • In agreement with this observation, treatment of mouse neuroblastoma cells with leptomycin B to inhibit nuclear protein export by exportin1 resulted in accumulation of RGS4 in the nucleus of these cells [1].
  • As observed in COS-7 cells, RGS4 exhibited cytoplasmic localization in mouse neuroblastoma cells, and RGS10 exhibited nuclear localization in human glioma cells [1].
  • Deletion or alanine substitution of an N-terminal leucine repeat motif present in both RGS4 and RGS16, a domain identified as a nuclear export sequence in HIV Rev and other proteins, promoted nuclear localization of these proteins in COS-7 cells [1].
  • These observations suggest that RGS4 may be induced in the heart to regulate cell signalling pathways in response to hypertrophy, and support the existence of a negative feedback loop for the long-term regulation of hypertrophy [2].
  • RGS3 and RGS4 gene expression was markedly enhanced in two model systems of cardiac hypertrophy: growth factor-stimulated cultured neonatal rat cardiomyocytes and pulmonary artery-banded (PAB) mice [3].

Psychiatry related information on RGS4

  • We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression [4].
  • Differences in regional and subcellular localization of G(q/11) and RGS4 protein levels in Alzheimer's disease: correlation with muscarinic M1 receptor binding parameters [5].

High impact information on RGS4

  • GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits [6].
  • RGS4 activates the GTPase activity of certain Gi alpha 1 mutants (e.g., R178C), but not others (e.g., Q204L) [6].
  • Purified RGS4 protein alone inhibited GTP-induced K(G) channel activity in inside-out patches from atrial myocytes [7].
  • Features of the N-terminal domain other than palmitoylation are responsible for the plasma membrane association of RGS4 and its ability to inhibit pheromone response in yeast [8].
  • Surprisingly, mutation of the cysteine residues within the N-terminal domain of RGS4 did not affect plasma membrane localization in yeast or the ability to inhibit signaling [8].

Chemical compound and disease context of RGS4


Biological context of RGS4

  • We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts [4].
  • Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC [4].
  • These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia [4].
  • Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene [4].
  • Despite little or no effect on responses to maximal receptor activation, RGS4 produced effects on the magnitude, kinetics, and oscillatory behavior of Ca2+ signaling at submaximal levels that were consistent with those of RGS2 and -3 [10].

Anatomical context of RGS4

  • In contrast, RGS2 and RGS4 completely inhibit Gq-directed activation of phospholipase C in cell membranes [11].
  • RGS2 selectively binds Gqalpha, but not other Galpha proteins (Gi, Go, Gs, G12/13) in brain membranes; RGS4 binds Gqalpha and Gialpha family members [11].
  • We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection [4].
  • Levels of RGS3 and RGS4 mRNA were found to be significantly upregulated in unused donor and end-stage failing myocardium (P < 0.05 and 0.01, and P < 0.05 and 0.02, respectively) compared to non-failing hearts [2].
  • N-terminally green fluorescent protein (GFP)-tagged regulator of G protein signaling (RGS) 2 and RGS4 fusion proteins expressed in human embryonic kidney 293 cells localized to the nucleus and cytosol, respectively [12].

Associations of RGS4 with chemical compounds

  • Binding of beta'-COP to RGS4 occurred through two dilysine motifs in RGS4, similar to those contained in some aminoglycoside antibiotics that are known to bind coatomer [13].
  • Although gross indices of signaling were unaffected by RGS4, it slowed the rate of increase in Ins(1,4,5)P3 levels [10].
  • They were selectively recruited to the plasma membrane by G proteins and correspondingly by receptors that activate those G proteins: GFP-RGS2 when coexpressed with Galphas, beta2-adrenergic receptor, Galphaq, or AT1A angiotensin II receptor, and GFP-RGS4 when coexpressed with Galphai2 or M2 muscarinic receptor [12].
  • N-Terminal Residues Control Proteasomal Degradation of RGS2, RGS4, and RGS5 in Human Embryonic Kidney 293 Cells [14].
  • These processes all appear to be energetically driven by the amphipathic N-terminal domain of RGS4 and are accelerated by palmitoylation of cysteine residues in this region [15].

Physical interactions of RGS4

  • However, these mGluR1a/Galphaq/11 interactions are not antagonized by the overexpression of either GRK2 mutants defective in Galphaq/11 binding or RGS4 [16].
  • We report here the determinants mediating selective association of RGS4 with several G protein-coupled receptors (GPCRs) that form macromolecular complexes with neuronal G protein-gated inwardly rectifying potassium (Kir3 or GIRK) channels [17].
  • The utility of the MS/NMR assay is demonstrated with the use of the catalytic fragment of human fibroblast collagenase (MMP-1) as a target protein and the screening of a library consisting of approximately 32 000 compounds for the identification of molecules that exhibit specific binding to the RGS4 protein [18].

Regulatory relationships of RGS4


Other interactions of RGS4

  • When reconstituted with phospholipid vesicles, RGS2 is 10-fold more potent than RGS4 in blocking Gqalpha-directed activation of phospholipase Cbeta1 [11].
  • Palmitoylated RGS16 or RGS4 WT but not C98A or C95A preincubated with membranes expressing 5-HT1a/G alpha o1 displayed increased GAP activity over time [20].
  • RGS3 and RGS3CT had G(qalpha) GAP activity similar to that of RGS4 [21].
  • This showed a more prominent role of variants from the loci AKT1, BDNF and RGS4 [22].
  • The proteins share a homologous core domain but have divergent amino-terminal sequences that are the site of palmitoylation for RGS-GAIP and RGS4 [23].

Analytical, diagnostic and therapeutic context of RGS4

  • Endogenous cytosolic RGS4 from NG108 cells and RGS2 from HEK293T cells cofractionated with the COPI complex by gel filtration [13].
  • An up-regulation of RGS4 expression has been consistently found in human heart failure and some animal models [24].
  • This RGS protein and RGS4 are reported to be expressed predominantly in brain, and in situ hybridization studies have revealed similarities in the regional distribution of RGS and G(alpha q) mRNA expression [25].
  • The expression of RGS4 mRNA in CHO cells was confirmed using RT PCR and successful knockdown of each was confirmed by western blot analysis or quantitative PCR [26].
  • Comparable protein-protein interactions between Gialpha1-GDP-AlF4- and the RGS domain or full-length RGS4 were detected using surface plasmon resonance [27].


  1. Cytoplasmic, nuclear, and golgi localization of RGS proteins. Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs. Chatterjee, T.K., Fisher, R.A. J. Biol. Chem. (2000) [Pubmed]
  2. Expression of RGS3, RGS4 and Gi alpha 2 in acutely failing donor hearts and end-stage heart failure. Owen, V.J., Burton, P.B., Mullen, A.J., Birks, E.J., Barton, P., Yacoub, M.H. Eur. Heart J. (2001) [Pubmed]
  3. RGS3 and RGS4 are GTPase activating proteins in the heart. Zhang, S., Watson, N., Zahner, J., Rottman, J.N., Blumer, K.J., Muslin, A.J. J. Mol. Cell. Cardiol. (1998) [Pubmed]
  4. RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity. Lipska, B.K., Mitkus, S., Caruso, M., Hyde, T.M., Chen, J., Vakkalanka, R., Straub, R.E., Weinberger, D.R., Kleinman, J.E. Hum. Mol. Genet. (2006) [Pubmed]
  5. Differences in regional and subcellular localization of G(q/11) and RGS4 protein levels in Alzheimer's disease: correlation with muscarinic M1 receptor binding parameters. Muma, N.A., Mariyappa, R., Williams, K., Lee, J.M. Synapse (2003) [Pubmed]
  6. GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. Berman, D.M., Wilkie, T.M., Gilman, A.G. Cell (1996) [Pubmed]
  7. PIP3 inhibition of RGS protein and its reversal by Ca2+/calmodulin mediate voltage-dependent control of the G protein cycle in a cardiac K+ channel. Ishii, M., Inanobe, A., Kurachi, Y. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  8. Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae. Srinivasa, S.P., Bernstein, L.S., Blumer, K.J., Linder, M.E. Proc. Natl. Acad. Sci. U.S.A. (1998) [Pubmed]
  9. Activation of extracellular signal-regulated kinase (ERK) and Akt by human serotonin 5-HT(1B) receptors in transfected BE(2)-C neuroblastoma cells is inhibited by RGS4. Leone, A.M., Errico, M., Lin, S.L., Cowen, D.S., Lione, A.M. J. Neurochem. (2000) [Pubmed]
  10. Single-cell imaging of intracellular Ca2+ and phospholipase C activity reveals that RGS 2, 3, and 4 differentially regulate signaling via the Galphaq/11-linked muscarinic M3 receptor. Tovey, S.C., Willars, G.B. Mol. Pharmacol. (2004) [Pubmed]
  11. RGS2/G0S8 is a selective inhibitor of Gqalpha function. Heximer, S.P., Watson, N., Linder, M.E., Blumer, K.J., Hepler, J.R. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  12. Recruitment of RGS2 and RGS4 to the plasma membrane by G proteins and receptors reflects functional interactions. Roy, A.A., Lemberg, K.E., Chidiac, P. Mol. Pharmacol. (2003) [Pubmed]
  13. RGS4 and RGS2 bind coatomer and inhibit COPI association with Golgi membranes and intracellular transport. Sullivan, B.M., Harrison-Lavoie, K.J., Marshansky, V., Lin, H.Y., Kehrl, J.H., Ausiello, D.A., Brown, D., Druey, K.M. Mol. Biol. Cell (2000) [Pubmed]
  14. N-Terminal Residues Control Proteasomal Degradation of RGS2, RGS4, and RGS5 in Human Embryonic Kidney 293 Cells. Bodenstein, J., Sunahara, R.K., Neubig, R.R. Mol. Pharmacol. (2007) [Pubmed]
  15. Binding of regulator of G protein signaling (RGS) proteins to phospholipid bilayers. Contribution of location and/or orientation to Gtpase-activating protein activity. Tu, Y., Woodson, J., Ross, E.M. J. Biol. Chem. (2001) [Pubmed]
  16. G Protein-coupled receptor kinase 2 regulator of G protein signaling homology domain binds to both metabotropic glutamate receptor 1a and Galphaq to attenuate signaling. Dhami, G.K., Dale, L.B., Anborgh, P.H., O'Connor-Halligan, K.E., Sterne-Marr, R., Ferguson, S.S. J. Biol. Chem. (2004) [Pubmed]
  17. RGS3 and RGS4 Differentially Associate with G Protein-coupled Receptor-Kir3 Channel Signaling Complexes Revealing Two Modes of RGS Modulation: PRECOUPLING AND COLLISION COUPLING. Ja??n, C., Doupnik, C.A. J. Biol. Chem. (2006) [Pubmed]
  18. MS/NMR: a structure-based approach for discovering protein ligands and for drug design by coupling size exclusion chromatography, mass spectrometry, and nuclear magnetic resonance spectroscopy. Moy, F.J., Haraki, K., Mobilio, D., Walker, G., Powers, R., Tabei, K., Tong, H., Siegel, M.M. Anal. Chem. (2001) [Pubmed]
  19. RGS4 inhibits platelet-activating factor receptor phosphorylation and cellular responses. Richardson, R.M., Marjoram, R.J., Barr, A.J., Snyderman, R. Biochemistry (2001) [Pubmed]
  20. Palmitoylation regulates regulator of G-protein signaling (RGS) 16 function. II. Palmitoylation of a cysteine residue in the RGS box is critical for RGS16 GTPase accelerating activity and regulation of Gi-coupled signalling. Osterhout, J.L., Waheed, A.A., Hiol, A., Ward, R.J., Davey, P.C., Nini, L., Wang, J., Milligan, G., Jones, T.L., Druey, K.M. J. Biol. Chem. (2003) [Pubmed]
  21. RGS3 is a GTPase-activating protein for g(ialpha) and g(qalpha) and a potent inhibitor of signaling by GTPase-deficient forms of g(qalpha) and g(11alpha). Scheschonka, A., Dessauer, C.W., Sinnarajah, S., Chidiac, P., Shi, C.S., Kehrl, J.H. Mol. Pharmacol. (2000) [Pubmed]
  22. A summary statistic approach to sequence variation in noncoding regions of six schizophrenia-associated gene loci. Winantea, J., Hoang, M.N., Ohlraun, S., Rietschel, M., Cichon, S., Propping, P., Nöthen, M.M., Freudenberg, J., Freudenberg-Hua, Y. Eur. J. Hum. Genet. (2006) [Pubmed]
  23. Amino-terminal cysteine residues of RGS16 are required for palmitoylation and modulation of Gi- and Gq-mediated signaling. Druey, K.M., Ugur, O., Caron, J.M., Chen, C.K., Backlund, P.S., Jones, T.L. J. Biol. Chem. (1999) [Pubmed]
  24. Regulators of G-protein signalling: multifunctional proteins with impact on signalling in the cardiovascular system. Wieland, T., Mittmann, C. Pharmacol. Ther. (2003) [Pubmed]
  25. RGS7 attenuates signal transduction through the G(alpha q) family of heterotrimeric G proteins in mammalian cells. Shuey, D.J., Betty, M., Jones, P.G., Khawaja, X.Z., Cockett, M.I. J. Neurochem. (1998) [Pubmed]
  26. Knock-down of RGS4 and beta tubulin in CHO cells expressing the human MT1 melatonin receptor prevents melatonin-induced receptor desensitization. Witt-Enderby, P.A., Jarzynka, M.J., Krawitt, B.J., Melan, M.A. Life Sci. (2004) [Pubmed]
  27. The regulators of G protein signaling (RGS) domains of RGS4, RGS10, and GAIP retain GTPase activating protein activity in vitro. Popov, S., Yu, K., Kozasa, T., Wilkie, T.M. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
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