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Gene Review

Rgs4  -  regulator of G-protein signaling 4

Mus musculus

Synonyms: AA004315, AA597169, ESTM48, ESTM50, RGS4, ...
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Disease relevance of Rgs4


High impact information on Rgs4

  • This adaptation was attributable to the upregulation of RGS4-an autoreceptor-associated, GTPase-accelerating protein [1].
  • RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion [1].
  • Moreover, Homer 2 preferentially bound to PLCbeta in pancreatic acini and brain extracts and stimulated GAP activity of RGS4 and of PLCbeta in an in vitro reconstitution system, with minimal effect on PLCbeta-mediated PIP2 hydrolysis [4].
  • We propose a model in which the sequential modifications of RGS4, RGS5, and RGS16 (N-terminal exposure of their Cys-2, its oxidation, and subsequent arginylation) act as a licensing mechanism in response to extracellular and intracellular signals before the targeting for proteolysis by UBR1 and UBR2 [5].
  • Here, we describe a mouse line deficient for Rgs4, a gene normally expressed early on in discrete populations of differentiating neurons and later on at multiple sites of the central nervous system, the cortex in particular, where it is one of the most highly transcribed Rgs genes [6].

Biological context of Rgs4

  • Generation of compound transgenic mice demonstrated that cardiac RGS4 overexpression ameliorated the cardiomyopathic phenotype that occurred as a result of PPAR-alpha overexpression without affecting the metabolic abnormalities seen in these hearts [7].
  • We therefore propose RGS4 as a novel antagonist of epithelial and endothelial cell tubulogenesis that selectively antagonizes intracellular signaling by G proteins and VEGF, thereby inhibiting cell proliferation, migration, and invasion, and VEGF and KDR expression [8].

Anatomical context of Rgs4


Associations of Rgs4 with chemical compounds

  • RGS4 transgenic mice were resistant to STZ-induced cardiac fetal gene induction [7].
  • RGS4 inhibits signaling by group I metabotropic glutamate receptors [11].
  • In Xenopus oocytes, purified RGS4 virtually abolishes the mGluR1a- and mGluR5a-mediated but not the inositol trisphospate-mediated activation of a calcium-dependent chloride current [11].
  • Radiochemical sequencing indicated that the N-terminal methionine of the lysate-produced RGS4 was replaced with arginine [12].
  • Since N-terminal arginine is a destabilizing residue not encoded by RGS4 mRNA, we conclude that the degron of RGS4 is generated through the removal of N-terminal methionine and enzymatic arginylation of the resulting N-terminal cysteine [12].

Regulatory relationships of Rgs4

  • Accordingly, RGS4 overexpression delayed and altered lung epithelial cell tubulation by selectively inhibiting G protein-mediated p38 MAPK activation, and, consequently, by reducing epithelial cell proliferation, migration, and expression of vascular endothelial growth factor (VEGF) [8].

Other interactions of Rgs4

  • Rgs4 mRNA expression is decreased in the brain of Fmr1 knockout mouse [13].
  • RGS4 and RGS5 are in vivo substrates of the N-end rule pathway [5].
  • The same pattern of receptor-selective inhibition by RGS4 was observed in acinar cells from wild type and several single and double Gq class knockout mice [14].
  • Finally, we found that RGS4 reduced endothelial cell response to VEGF by decreasing VEGF receptor-2 (KDR) expression [8].
  • Consistent with a required role for GTP-bound G(q)/G(11), expression of the regulators of G protein signaling (RGS4 and RGS16) also attenuated insulin-stimulated GLUT4-EGFP translocation [15].

Analytical, diagnostic and therapeutic context of Rgs4

  • We performed microarray analysis to further our understanding of tubulogenesis and observed a robust induction of regulator of G protein signaling 4 (RGS4) mRNA expression solely in tubulating cells, thereby implicating RGS4 as a potential regulator of tubulogenesis [8].
  • Distribution of RGS4 mRNA in mouse brain shown by in situ hybridization [10].
  • Overexpression of RGS4 in postnatal ventricular tissue did not affect cardiac morphology or basal cardiac function, but markedly compromised the ability of the heart to adapt to transverse aortic constriction (TAC) [2].


  1. 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]
  2. RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload. Rogers, J.H., Tamirisa, P., Kovacs, A., Weinheimer, C., Courtois, M., Blumer, K.J., Kelly, D.P., Muslin, A.J. J. Clin. Invest. (1999) [Pubmed]
  3. RGS4 reduces contractile dysfunction and hypertrophic gene induction in Galpha q overexpressing mice. Rogers, J.H., Tsirka, A., Kovacs, A., Blumer, K.J., Dorn, G.W., Muslin, A.J. J. Mol. Cell. Cardiol. (2001) [Pubmed]
  4. Homer 2 tunes G protein-coupled receptors stimulus intensity by regulating RGS proteins and PLCbeta GAP activities. Shin, D.M., Dehoff, M., Luo, X., Kang, S.H., Tu, J., Nayak, S.K., Ross, E.M., Worley, P.F., Muallem, S. J. Cell Biol. (2003) [Pubmed]
  5. RGS4 and RGS5 are in vivo substrates of the N-end rule pathway. Lee, M.J., Tasaki, T., Moroi, K., An, J.Y., Kimura, S., Davydov, I.V., Kwon, Y.T. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. Generation and characterization of Rgs4 mutant mice. Grillet, N., Pattyn, A., Contet, C., Kieffer, B.L., Goridis, C., Brunet, J.F. Mol. Cell. Biol. (2005) [Pubmed]
  7. G-protein signaling participates in the development of diabetic cardiomyopathy. Harris, I.S., Treskov, I., Rowley, M.W., Heximer, S., Kaltenbronn, K., Finck, B.N., Gross, R.W., Kelly, D.P., Blumer, K.J., Muslin, A.J. Diabetes (2004) [Pubmed]
  8. Identification and characterization of regulator of G protein signaling 4 (RGS4) as a novel inhibitor of tubulogenesis: RGS4 inhibits mitogen-activated protein kinases and vascular endothelial growth factor signaling. Albig, A.R., Schiemann, W.P. Mol. Biol. Cell (2005) [Pubmed]
  9. Morphine alters the selective association between mu-opioid receptors and specific RGS proteins in mouse periaqueductal gray matter. Garzón, J., Rodríguez-Muñoz, M., Sánchez-Blázquez, P. Neuropharmacology (2005) [Pubmed]
  10. Distribution of RGS4 mRNA in mouse brain shown by in situ hybridization. Nomoto, S., Adachi, K., Yang, L.X., Hirata, Y., Muraguchi, S., Kiuchi, K. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  11. RGS4 inhibits signaling by group I metabotropic glutamate receptors. Saugstad, J.A., Marino, M.J., Folk, J.A., Hepler, J.R., Conn, P.J. J. Neurosci. (1998) [Pubmed]
  12. RGS4 is arginylated and degraded by the N-end rule pathway in vitro. Davydov, I.V., Varshavsky, A. J. Biol. Chem. (2000) [Pubmed]
  13. Rgs4 mRNA expression is decreased in the brain of Fmr1 knockout mouse. Tervonen, T., Akerman, K., Oostra, B.A., Castrén, M. Brain Res. Mol. Brain Res. (2005) [Pubmed]
  14. RGS proteins determine signaling specificity of Gq-coupled receptors. Xu, X., Zeng, W., Popov, S., Berman, D.M., Davignon, I., Yu, K., Yowe, D., Offermanns, S., Muallem, S., Wilkie, T.M. J. Biol. Chem. (1999) [Pubmed]
  15. The trimeric GTP-binding protein (G(q)/G(11)) alpha subunit is required for insulin-stimulated GLUT4 translocation in 3T3L1 adipocytes. Kanzaki, M., Watson, R.T., Artemyev, N.O., Pessin, J.E. J. Biol. Chem. (2000) [Pubmed]
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