regulator of G-protein signaling 4 | R4 family | IUPHAR/BPS Guide to PHARMACOLOGY

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regulator of G-protein signaling 4

Target id: 2811

Nomenclature: regulator of G-protein signaling 4

Abbreviated Name: RGS4

Family: R4 family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for regulator of G-protein signaling 4 in GtoImmuPdb

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 302 1q23.3 RGS4 regulator of G protein signaling 4
Mouse - 205 1 H3 Rgs4 regulator of G-protein signaling 4
Rat - 205 13q24 Rgs4 regulator of G-protein signaling 4
Previous and Unofficial Names
ESTM48 | ESTM50
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Associated Proteins
G Proteins
Name References
Gz 16
Gαq/11 1,16
Gαs
Golf
Gαi/0 1-2,16
Gα12/13
Interacting Proteins
Name Effect References
calmodulin Reverses PIP3-mediated GAP inhibition 30
GPCR-Kir3 channel complex Accelerated GIRK activation and deactivation 17
μ receptor Reduced agonist potency G-protein-coupling specificity 13,23
δ receptor G-protein-coupling specificity 13,23
Gβγ and PLCβ1 Signaling complex formation 11
spinophilin Scaffolding 25,42
Associated Protein Comments
Affinity for Gαq is lower than that for Gαi.

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
RGS4 inhibitor 11b Hs Inhibition 7.8 pIC50 41
pIC50 7.8 (IC50 1.44x10-8 M) [41]
Description: Inhibition of Gαo binding
CCG-50014 Hs Inhibition 7.5 pIC50 4,41
pIC50 7.5 (IC50 3.01x10-8 M) [4,41]
Description: Inhibition of Gαo binding.
RGS4 inhibitor 13 Hs Inhibition 7.3 pIC50 41
pIC50 7.3 (IC50 5.43x10-8 M) [41]
Description: Inhibition of Gαo binding
CCG-63808 Hs Inhibition 5.0 – 5.8 pIC50 3
pIC50 5.0 – 5.8 (IC50 1x10-5 – 1.4x10-6 M) [3]
Description: Inhibition of Gαo binding. The higher affinity value was measured using TR-FRET, the lower value using flow cytometry protein interaction assay (FCPIA).
CCG-63802 Hs Inhibition 5.1 – 5.7 pIC50 3
pIC50 5.1 – 5.7 (IC50 9x10-6 – 1.9x10-6 M) [3]
Description: Inhibition of Gαo binding. The higher affinity value was measured using TR-FRET, the lower value using flow cytometry protein interaction assay (FCPIA).
(4Z)-1-(3-fluorophenyl)-4-(2-oxo-1H-indol-3-ylidene)pyrazolidine-3,5-dione Hs Inhibition 5.1 pIC50 39
pIC50 5.1 (IC50 8.2x10-6 M) [39]
CCG-4986 Hs Inhibition 4.7 – 5.4 pIC50 19,31-32
pIC50 4.7 – 5.4 (IC50 1.8x10-5 – 4.2x10-6 M) [19,31-32]
Description: Inhibition of Gαo binding.
YJ34 Rn Inhibition 4.6 – 5.1 pIC50 18,33
pIC50 4.6 – 5.1 (IC50 2.6x10-5 – 9x10-6 M) [18,33]
Description: Inhibition of Gαo binding.
(5Z)-5-[(5-bromothiophen-2-yl)methylidene]-1-methyl-2-sulfanylidene-1,3-diazinane-4,6-dione Hs Inhibition 4.8 pIC50 39
pIC50 4.8 (IC50 1.53x10-5 M) [39]
(5E)-1-(4-fluorophenyl)-5-[(5-methylthiophen-2-yl)methylidene]-2-sulfanylidene-1,3-diazinane-4,6-dione Hs Inhibition 4.7 pIC50 39
pIC50 4.7 (IC50 1.83x10-5 M) [39]
(5Z)-1-(2-fluorophenyl)-2-sulfanylidene-5-(thiophen-2-ylmethylidene)-1,3-diazinane-4,6-dione Hs Inhibition 4.6 pIC50 39
pIC50 4.6 (IC50 2.75x10-5 M) [39]
5nd Rn Inhibition 4.6 pIC50 34
pIC50 4.6 (IC50 2.8x10-5 M) [34]
Description: Inhibition of Gαo binding.
View species-specific inhibitor tables
Tissue Distribution
High expression in brain, low/moderate expression in heart. Within brain: gyrus areas of cortex and hippocampus, hippocampus, putamen, and striatum.
Species:  Human
Technique:  Quantitative RT-PCR.
References:  21
Cortex, striatum, thalamus, hippocampus.
Species:  Rat
Technique:  In situ hybridisation.
References:  14
Functional Assays
Single turnover GTPase assay (measured in human and rat).
Species:  Human
Tissue:  Biochemical assay.
Response measured:  Measuring GTPase activity using γ[32P]GTP.
References:  32-33,39
Malachite Green Assay.
Species:  Rat
Tissue:  Biochemical assay.
Response measured:  Increase in free inorganic phosphate; measuring GTPase activity.
References:  27,39
Fluo4 NW calcium signaling assay.
Species:  Human
Tissue:  HEK-293 FlpIn-TREx; HEK-293T cells.
Response measured:  RGS4-mediated decrease in muscarinic M3 receptor-induced calcium transient.
References:  5,39
TR-FRET (assayed in human and rat).
Species:  Human
Tissue:  Biochemical assay.
Response measured:  Assay measuring protein-protein interaction between RGS4 and Gα.
References:  3
Transcreener GDP assay.
Species:  Human
Tissue:  Biochemical asay.
Response measured:  Measuring GTPase activity.
References:  44
Flow cytometry protein interaction assay.
Species:  Rat
Tissue:  Biochemical assay.
Response measured:  Fluorophore-labeled Gα binds to biotinylated RGS4 linked to LumAvidin beads; measurement of bead-associated fluorescence. 
References:  32
Physiological Functions
Limits opioid-induced analgesia.
Species:  Mouse
Tissue:  Central nervous system (CNS).
References:  12
Inhibits phenylephrine- and endothelin-1-mediated signaling.
Species:  Rat
Tissue:  Cardiomyocytes.
References:  40
Regulates parasympathetic signaling in sinoatrial node.
Species:  Mouse
Tissue:  Heart, sinoatrial node.
References:  9
Negatively regulates insulin release, in vitro and in vivo.
Species:  Mouse
Tissue:  Pancreatic beta cells.
References:  35
Attenuates Gq-mediated PLCβ activation.
Species:  Human
Tissue:  Recombinant cells (NG-108).   
References:  16
Can accelerate activation and desensitization of GIRK channels.
Species:  Human
Tissue:  Exogenous expression in Xenopus oocytes.
References:  8
Physiological Consequences of Altering Gene Expression
RGS4 knockout mice have lower bodyweight and shorter duration before falling off of rotating rod.
Species:  Mouse
Tissue: 
Technique:  Gene knockout.
References:  15
RGS4 knockout mice have increased PGE(2)-induced Muc5ac production.
Species:  Mouse
Tissue:  Airway.
Technique:  Gene knockout.
References:  38
Exogenous RGS4 expression in MDA-MB-231 cells slows tumor growth, by inhibiting tumor growth, and suppressing invasiveness.
Species:  Human
Tissue:  MDA-MB-231, implanted in mouse (xenograft).
Technique: 
References:  43
RGS4 knockout mice are more sensitive to CsA-induced renal failure.
Species:  Mouse
Tissue:  Kidney.
Technique:  Gene knockout.
References:  36
Involved in the generation of abnormal involuntary movements (AIMs) in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease. RGS4 mRNA is elevated by L-DOPA treatment and suppressing this elevation during L-DOPA priming reduces the induction of AIMs.
Species:  Rat
Tissue:  Striatum.
Technique:  RNA interference.
References:  20
Involved in the generation of abnormal involuntary movements in the unilateral 6-OHDA-lesioned rat and mouse models of Parkinson's disease. In contrast to wild-type mice, RGS4⁻/⁻ mice exhibited normal eCB-LTD after dopamine depletion and were significantly less impaired in the 6-OHDA model of Parkinson's disease.    
Species:  Mouse
Tissue:  Striatum.
Technique:  Gene knockout.
References:  24
Loss of RGS4 promotes abnormal calcium release and is associated with atrial fibrillation. Attributed to enhanced activity in the Gαq/11- IP3 pathway resulting in abnormal Ca2+ release and corresponding electrical events.
Species:  Mouse
Tissue:  Heart, atrial cells.
Technique:  Gene knockout.
References:  29
Xenobiotics Influencing Gene Expression
RGS4 protein levels are increased by inhibitors of the proteasome, such as MG-132.   
Species:  Human
Tissue:  HEK-293 cells.
Technique:  Western blot and PathHunter ProLabel β-gal complementation assay.
References:  5,37
Clinically-Relevant Mutations and Pathophysiology
Disease:  Parkinson Disease
Synonyms: Parkinson's disease [Disease Ontology: DOID:14330]
Disease Ontology: DOID:14330
OMIM: 168600
References:  20,24
Disease:  Schizophrenia
Disease Ontology: DOID:5419
OMIM: 181500
Orphanet: ORPHA3140
References:  6-7,26,28
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Description:  Reduction in RGS4 isoform 3 splice variant associated with schizophrenia.
Amino acids:  187
Protein accession: 
References:  10
Type:  Single nucleotide polymorphism
Species:  Human
Description:  The RGS4 3′ UTR SNP, rs10759 is associated with risk of bladder cancer.
SNP accession: 
References:  22

References

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1. Berman DM, Kozasa T, Gilman AG. (1996) The GTPase-activating protein RGS4 stabilizes the transition state for nucleotide hydrolysis. J. Biol. Chem., 271 (44): 27209-12. [PMID:8910288]

2. Berman DM, Wilkie TM, Gilman AG. (1996) GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. Cell, 86 (3): 445-52. [PMID:8756726]

3. Blazer LL, Roman DL, Chung A, Larsen MJ, Greedy BM, Husbands SM, Neubig RR. (2010) Reversible, allosteric small-molecule inhibitors of regulator of G protein signaling proteins. Mol. Pharmacol., 78 (3): 524-33. [PMID:20571077]

4. Blazer LL, Zhang H, Casey EM, Husbands SM, Neubig RR. (2011) A nanomolar-potency small molecule inhibitor of regulator of G-protein signaling proteins. Biochemistry, 50 (15): 3181-92. [PMID:21329361]

5. Bodenstein J, Sunahara RK, Neubig RR. (2007) N-terminal residues control proteasomal degradation of RGS2, RGS4, and RGS5 in human embryonic kidney 293 cells. Mol. Pharmacol., 71 (4): 1040-50. [PMID:17220356]

6. Chen X, Dunham C, Kendler S, Wang X, O'Neill FA, Walsh D, Kendler KS. (2004) Regulator of G-protein signaling 4 (RGS4) gene is associated with schizophrenia in Irish high density families. Am. J. Med. Genet. B Neuropsychiatr. Genet., 129B (1): 23-6. [PMID:15274033]

7. Chowdari KV, Mirnics K, Semwal P, Wood J, Lawrence E, Bhatia T, Deshpande SN, B K T, Ferrell RE, Middleton FA et al.. (2002) Association and linkage analyses of RGS4 polymorphisms in schizophrenia. Hum. Mol. Genet., 11 (12): 1373-80. [PMID:12023979]

8. Chuang HH, Yu M, Jan YN, Jan LY. (1998) Evidence that the nucleotide exchange and hydrolysis cycle of G proteins causes acute desensitization of G-protein gated inward rectifier K+ channels. Proc. Natl. Acad. Sci. U.S.A., 95 (20): 11727-32. [PMID:9751733]

9. Cifelli C, Rose RA, Zhang H, Voigtlaender-Bolz J, Bolz SS, Backx PH, Heximer SP. (2008) RGS4 regulates parasympathetic signaling and heart rate control in the sinoatrial node. Circ. Res., 103 (5): 527-35. [PMID:18658048]

10. Ding L, Hegde AN. (2009) Expression of RGS4 splice variants in dorsolateral prefrontal cortex of schizophrenic and bipolar disorder patients. Biol. Psychiatry, 65 (6): 541-5. [PMID:19041089]

11. Dowal L, Elliott J, Popov S, Wilkie TM, Scarlata S. (2001) Determination of the contact energies between a regulator of G protein signaling and G protein subunits and phospholipase C beta 1. Biochemistry, 40 (2): 414-21. [PMID:11148035]

12. Garzón J, Rodríguez-Muñoz M, de la Torre-Madrid E, Sánchez-Blázquez P. (2005) Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid receptors in the CNS. Psychopharmacology (Berl.), 180 (1): 1-11. [PMID:15830230]

13. Georgoussi Z, Leontiadis L, Mazarakou G, Merkouris M, Hyde K, Hamm H. (2006) Selective interactions between G protein subunits and RGS4 with the C-terminal domains of the mu- and delta-opioid receptors regulate opioid receptor signaling. Cell. Signal., 18 (6): 771-82. [PMID:16120478]

14. Gold SJ, Ni YG, Dohlman HG, Nestler EJ. (1997) Regulators of G-protein signaling (RGS) proteins: region-specific expression of nine subtypes in rat brain. J. Neurosci., 17 (20): 8024-37. [PMID:9315921]

15. Grillet N, Pattyn A, Contet C, Kieffer BL, Goridis C, Brunet JF. (2005) Generation and characterization of Rgs4 mutant mice. Mol. Cell. Biol., 25 (10): 4221-8. [PMID:15870291]

16. Heximer SP, Watson N, Linder ME, Blumer KJ, Hepler JR. (1997) RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proc. Natl. Acad. Sci. U.S.A., 94 (26): 14389-93. [PMID:9405622]

17. Jaén C, Doupnik CA. (2006) RGS3 and RGS4 differentially associate with G protein-coupled receptor-Kir3 channel signaling complexes revealing two modes of RGS modulation. Precoupling and collision coupling. J. Biol. Chem., 281 (45): 34549-60. [PMID:16973624]

18. Jin Y, Zhong H, Omnaas JR, Neubig RR, Mosberg HI. (2004) Structure-based design, synthesis, and pharmacologic evaluation of peptide RGS4 inhibitors. J. Pept. Res., 63 (2): 141-6. [PMID:15009535]

19. Kimple AJ, Willard FS, Giguère PM, Johnston CA, Mocanu V, Siderovski DP. (2007) The RGS protein inhibitor CCG-4986 is a covalent modifier of the RGS4 Galpha-interaction face. Biochim. Biophys. Acta, 1774 (9): 1213-20. [PMID:17660054]

20. Ko WK, Martin-Negrier ML, Bezard E, Crossman AR, Ravenscroft P. (2014) RGS4 is involved in the generation of abnormal involuntary movements in the unilateral 6-OHDA-lesioned rat model of Parkinson's disease. Neurobiol. Dis., 70: 138-48. [PMID:24969021]

21. Larminie C, Murdock P, Walhin JP, Duckworth M, Blumer KJ, Scheideler MA, Garnier M. (2004) Selective expression of regulators of G-protein signaling (RGS) in the human central nervous system. Brain Res. Mol. Brain Res., 122 (1): 24-34. [PMID:14992813]

22. Lee EK, Ye Y, Kamat AM, Wu X. (2013) Genetic variations in regulator of G-protein signaling (RGS) confer risk of bladder cancer. Cancer, 119 (9): 1643-51. [PMID:23529717]

23. Leontiadis LJ, Papakonstantinou MP, Georgoussi Z. (2009) Regulator of G protein signaling 4 confers selectivity to specific G proteins to modulate mu- and delta-opioid receptor signaling. Cell. Signal., 21 (7): 1218-28. [PMID:19324084]

24. Lerner TN, Kreitzer AC. (2012) RGS4 is required for dopaminergic control of striatal LTD and susceptibility to parkinsonian motor deficits. Neuron, 73 (2): 347-59. [PMID:22284188]

25. Liu W, Yuen EY, Allen PB, Feng J, Greengard P, Yan Z. (2006) Adrenergic modulation of NMDA receptors in prefrontal cortex is differentially regulated by RGS proteins and spinophilin. Proc. Natl. Acad. Sci. U.S.A., 103 (48): 18338-43. [PMID:17101972]

26. Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P. (2001) Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol. Psychiatry, 6 (3): 293-301. [PMID:11326297]

27. Monroy CA, Mackie DI, Roman DL. (2013) A high throughput screen for RGS proteins using steady state monitoring of free phosphate formation. PLoS ONE, 8 (4): e62247. [PMID:23626793]

28. Morris DW, Rodgers A, McGhee KA, Schwaiger S, Scully P, Quinn J, Meagher D, Waddington JL, Gill M, Corvin AP. (2004) Confirming RGS4 as a susceptibility gene for schizophrenia. Am. J. Med. Genet. B Neuropsychiatr. Genet., 125B (1): 50-3. [PMID:14755443]

29. Opel A, Nobles M, Montaigne D, Finlay M, Anderson N, Breckenridge R, Tinker A. (2015) Absence of the Regulator of G-protein Signaling, RGS4, Predisposes to Atrial Fibrillation and Is Associated with Abnormal Calcium Handling. J. Biol. Chem., 290 (31): 19233-44. [PMID:26088132]

30. Popov SG, Krishna UM, Falck JR, Wilkie TM. (2000) Ca2+/Calmodulin reverses phosphatidylinositol 3,4, 5-trisphosphate-dependent inhibition of regulators of G protein-signaling GTPase-activating protein activity. J. Biol. Chem., 275 (25): 18962-8. [PMID:10747990]

31. Roman DL, Blazer LL, Monroy CA, Neubig RR. (2010) Allosteric inhibition of the regulator of G protein signaling-Galpha protein-protein interaction by CCG-4986. Mol. Pharmacol., 78 (3): 360-5. [PMID:20530129]

32. Roman DL, Talbot JN, Roof RA, Sunahara RK, Traynor JR, Neubig RR. (2007) Identification of small-molecule inhibitors of RGS4 using a high-throughput flow cytometry protein interaction assay. Mol. Pharmacol., 71 (1): 169-75. [PMID:17012620]

33. Roof RA, Jin Y, Roman DL, Sunahara RK, Ishii M, Mosberg HI, Neubig RR. (2006) Mechanism of action and structural requirements of constrained peptide inhibitors of RGS proteins. Chem Biol Drug Des, 67 (4): 266-74. [PMID:16629824]

34. Roof RA, Roman DL, Clements ST, Sobczyk-Kojiro K, Blazer LL, Ota S, Mosberg HI, Neubig RR. (2009) A covalent peptide inhibitor of RGS4 identified in a focused one-bead, one compound library screen. BMC Pharmacol., 9: 9. [PMID:19463173]

35. Ruiz de Azua I, Scarselli M, Rosemond E, Gautam D, Jou W, Gavrilova O, Ebert PJ, Levitt P, Wess J. (2010) RGS4 is a negative regulator of insulin release from pancreatic beta-cells in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A., 107 (17): 7999-8004. [PMID:20385802]

36. Siedlecki A, Anderson JR, Jin X, Garbow JR, Lupu TS, Muslin AJ. (2010) RGS4 controls renal blood flow and inhibits cyclosporine-mediated nephrotoxicity. Am. J. Transplant., 10 (2): 231-41. [PMID:19958325]

37. Sjögren B, Parra S, Heath LJ, Atkins KB, Xie ZJ, Neubig RR. (2012) Cardiotonic steroids stabilize regulator of G protein signaling 2 protein levels. Mol. Pharmacol., 82 (3): 500-9. [PMID:22695717]

38. Song KS, Choi YH, Kim JM, Lee H, Lee TJ, Yoon JH. (2009) Suppression of prostaglandin E2-induced MUC5AC overproduction by RGS4 in the airway. Am. J. Physiol. Lung Cell Mol. Physiol., 296 (4): L684-92. [PMID:19201815]

39. Storaska AJ, Mei JP, Wu M, Li M, Wade SM, Blazer LL, Sjögren B, Hopkins CR, Lindsley CW, Lin Z et al.. (2013) Reversible inhibitors of regulators of G-protein signaling identified in a high-throughput cell-based calcium signaling assay. Cell. Signal., 25 (12): 2848-55. [PMID:24041654]

40. Tamirisa P, Blumer KJ, Muslin AJ. (1999) RGS4 inhibits G-protein signaling in cardiomyocytes. Circulation, 99 (3): 441-7. [PMID:9918533]

41. Turner EM, Blazer LL, Neubig RR, Husbands SM. (2012) Small Molecule Inhibitors of Regulator of G Protein Signalling (RGS) Proteins. ACS Med Chem Lett, 3 (2): 146-150. [PMID:22368763]

42. Wang X, Zeng W, Soyombo AA, Tang W, Ross EM, Barnes AP, Milgram SL, Penninger JM, Allen PB, Greengard P et al.. (2005) Spinophilin regulates Ca2+ signalling by binding the N-terminal domain of RGS2 and the third intracellular loop of G-protein-coupled receptors. Nat. Cell Biol., 7 (4): 405-11. [PMID:15793568]

43. Xie Y, Wolff DW, Wei T, Wang B, Deng C, Kirui JK, Jiang H, Qin J, Abel PW, Tu Y. (2009) Breast cancer migration and invasion depend on proteasome degradation of regulator of G-protein signaling 4. Cancer Res., 69 (14): 5743-51. [PMID:19549919]

44. Zielinski T, Kimple AJ, Hutsell SQ, Koeff MD, Siderovski DP, Lowery RG. (2009) Two Galpha(i1) rate-modifying mutations act in concert to allow receptor-independent, steady-state measurements of RGS protein activity. J Biomol Screen, 14 (10): 1195-206. [PMID:19820068]

Contributors

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How to cite this page

Vincent Shaw, Benita Sjögren.
R4 family: regulator of G-protein signaling 4. Last modified on 08/05/2017. Accessed on 18/12/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2811.