RGS4

RGS4
Identifiers
Aliases	RGS4 , Rgs4, AA004315, AA597169, ESTM48, ESTM50, RGP4, SCZD9, regulator of G-protein signaling 4, regulator of G protein signaling 4
External IDs	OMIM: 602516; MGI: 108409; HomoloGene: 4100; GeneCards: RGS4; OMA:RGS4 - orthologs
Gene location (Human) Chr. Chromosome 1 (human) [1] Band 1q23.3 Start 163,068,775 bp [1] End 163,076,802 bp [1]
Gene location (Mouse) Chr. Chromosome 1 (mouse) [2] Band 1 H2.3|1 76.84 cM Start 169,569,046 bp [2] End 169,575,211 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in middle temporal gyrus Brodmann area 23 endothelial cell frontal pole orbitofrontal cortex superior frontal gyrus Brodmann area 46 primary visual cortex prefrontal cortex parietal lobe Top expressed in superior cervical ganglion facial motor nucleus prefrontal cortex superior frontal gyrus lateral geniculate nucleus spinal ganglia medial dorsal nucleus olfactory tubercle pontine nuclei mammillary body More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G-protein alpha-subunit binding calmodulin binding GTPase activator activity GTPase activity Cellular component cytoplasm cytosol plasma membrane membrane nucleus protein-containing complex Biological process positive regulation of GTPase activity negative regulation of signal transduction negative regulation of G protein-coupled receptor signaling pathway regulation of G protein-coupled receptor signaling pathway G protein-coupled receptor signaling pathway response to amphetamine brain development positive regulation of heart rate response to cocaine response to morphine response to ethanol regulation of calcium ion transport negative regulation of dopamine receptor signaling pathway negative regulation of cell growth involved in cardiac muscle cell development regulation of actin filament organization negative regulation of glycine import across plasma membrane regulation of potassium ion transmembrane transport negative regulation of potassium ion transmembrane transport dorsal root ganglion development positive regulation of excitatory postsynaptic potential Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 5999 19736 Ensembl ENSG00000117152 ENSMUSG00000038530 UniProt P49798 O08899 RefSeq (mRNA) NM_001102445 NM_001113380 NM_001113381 NM_005613 NM_009062 RefSeq (protein) NP_001095915 NP_001106851 NP_001106852 NP_005604 NP_005604.1 NP_033088 Location (UCSC) Chr 1: 163.07 – 163.08 Mb Chr 1: 169.57 – 169.58 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Regulator of G protein signaling 4 also known as RGP4 is a protein that in humans is encoded by the RGS4 gene. RGP4 regulates G protein signaling. ^[5]

Function

Regulator of G protein signalling (RGS) family members are regulatory molecules that act as GTPase activating proteins (GAPs) for G alpha subunits of heterotrimeric G proteins. ^[6] RGS proteins are able to deactivate G protein subunits of the G_i alpha, G_o alpha and G_q alpha subtypes. They drive G proteins into their inactive GDP-bound forms. Regulator of G protein signaling 4 belongs to this family. All RGS proteins share a conserved 120-amino acid sequence termed the RGS domain which conveys GAP activity. ^[7] Regulator of G protein signaling 4 protein is 37% identical to RGS1 and 97% identical to rat Rgs4. This protein negatively regulates signaling upstream or at the level of the heterotrimeric G protein and is localized in the cytoplasm. ^[5]

Clinical significance

A number of studies associate the RGS4 gene with schizophrenia, ^{[8] [9] [10] [11]} while some fail to detect an association. ^[12]

RGS4 is also of interest as one of the three main RGS proteins (along with RGS9 and RGS17) involved in terminating signalling by the mu opioid receptor, ^[13] and may be important in the development of tolerance to opioid drugs. ^{[14] [15] [16] [17] [18]}

Inhibitors

• cyclic peptides ^[19]
• CCG-4986 ^[20]

Interactions

RGS4 has been shown to interact with:

• COPB2, ^[21]
• ERBB3, ^[22] and
• GNAQ. ^{[23] [24]}

References

1. GRCh38: Ensembl release 89: ENSG00000117152 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000038530 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: RGS4 regulator of G-protein signalling 4".
6. Berman DM, Wilkie TM, Gilman AG (1996). "GAIP and RGS4 are GTPase-activating proteins for the G_i subfamily of G protein alpha subunits". Cell. 86 (3): 445–52. doi: 10.1016/S0092-8674(00)80117-8 . PMID   8756726. S2CID   12427406.
7. Popov S, Yu K, Kozasa T, Wilkie TM (July 1997). "The regulators of G protein signaling (RGS) domains of RGS4, RGS10, and GAIP retain GTPase activating protein activity in vitro". Proc. Natl. Acad. Sci. U.S.A. 94 (14): 7216–20. Bibcode:1997PNAS...94.7216P. doi: 10.1073/pnas.94.14.7216 . PMC   23796 . PMID   9207071.
8. Stefanis NC, Trikalinos TA, Avramopoulos D, Smyrnis N, Evdokimidis I, Ntzani EE, Hatzimanolis A, Ioannidis JP, Stefanis CN (2008). "Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level". Behavioral and Brain Functions. 4: 46. doi: 10.1186/1744-9081-4-46 . PMC   2572614 . PMID   18834502.
9. Prasad KM, Almasy L, Gur RC, Gur RE, Pogue-Geile M, Chowdari KV, Talkowski ME, Nimgaonkar VL (March 2009). "RGS4 Polymorphisms Associated With Variability of Cognitive Performance in a Family-Based Schizophrenia Sample". Schizophrenia Bulletin. 36 (5): 983–90. doi:10.1093/schbul/sbp002. PMC   2930339 . PMID   19282471.
10. Dean B, Boer S, Gibbons A, Money T, Scarr E (March 2009). "Recent advances in postmortem pathology and neurochemistry in schizophrenia". Current Opinion in Psychiatry. 22 (2): 154–60. doi:10.1097/YCO.0b013e328323d52e. PMID   19553869. S2CID   21346147.
11. Ding L, Hegde AN (March 2009). "Expression of RGS4 splice variants in dorsolateral prefrontal cortex of schizophrenic and bipolar disorder patients". Biological Psychiatry. 65 (6): 541–5. doi:10.1016/j.biopsych.2008.10.026. PMID   19041089. S2CID   21532854.
12. Stuart Gibbons A, Scarr E, McOmish CE, Hannan AJ, Thomas EA, Dean B (August 2008). "Regulator of G-protein signalling 4 expression is not altered in the prefrontal cortex in schizophrenia". The Australian and New Zealand Journal of Psychiatry. 42 (8): 740–5. doi:10.1080/00048670802206338. PMID   18622782. S2CID   205398396.
13. Hooks SB, Martemyanov K, Zachariou V (January 2008). "A role of RGS proteins in drug addiction". Biochemical Pharmacology . 75 (1): 76–84. doi:10.1016/j.bcp.2007.07.045. PMID   17880927.
14. Grillet N, Pattyn A, Contet C, Kieffer BL, Goridis C, Brunet JF (May 2005). "Generation and characterization of Rgs4 mutant mice". Molecular and Cellular Biology. 25 (10): 4221–8. doi:10.1128/MCB.25.10.4221-4228.2005. PMC   1087729 . PMID   15870291.
15. Garzón J, Rodríguez-Muñoz M, de la Torre-Madrid E, Sánchez-Blázquez P (June 2005). "Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid receptors in the CNS". Psychopharmacology. 180 (1): 1–11. doi:10.1007/s00213-005-2248-9. hdl: 10261/154655 . PMID   15830230. S2CID   21952312.
16. Georgoussi Z, Leontiadis L, Mazarakou G, Merkouris M, Hyde K, Hamm H (June 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". Cellular Signalling. 18 (6): 771–82. doi:10.1016/j.cellsig.2005.07.003. PMID   16120478.
17. Leontiadis LJ, Papakonstantinou MP, Georgoussi Z (July 2009). "Regulator of G protein signaling 4 confers selectivity to specific G proteins to modulate mu- and delta-opioid receptor signaling". Cellular Signalling. 21 (7): 1218–28. doi:10.1016/j.cellsig.2009.03.013. PMID   19324084.
18. Wang Q, Liu-Chen LY, Traynor JR (July 2009). "Differential Modulation of {micro}- and {delta}-Opioid Receptor Agonists by Endogenous RGS4 Protein in SH-SY5Y Cells". The Journal of Biological Chemistry. 284 (27): 18357–67. doi: 10.1074/jbc.M109.015453 . PMC   2709384 . PMID   19416973.
19. Jin Y, Zhong H, Omnaas JR, Neubig RR, Mosberg HI (2004). "Structure-based design, synthesis, and activity of peptide inhibitors of RGS4 GAP activity". Regulators of G-Protein Signaling, Part A. Methods in Enzymology. Vol. 389. pp. 266–77. doi:10.1016/S0076-6879(04)89016-5. ISBN   9780121827946. PMID   15313571.
20. Roman DL, Talbot JN, Roof RA, Sunahara RK, Traynor JR, Neubig RR (January 2007). "Identification of small-molecule inhibitors of RGS4 using a high-throughput flow cytometry protein interaction assay". Molecular Pharmacology. 71 (1): 169–75. doi:10.1124/mol.106.028670. PMID   17012620. S2CID   22699604.
21. Sullivan BM, Harrison-Lavoie KJ, Marshansky V, Lin HY, Kehrl JH, Ausiello DA, Brown D, Druey KM (2000). "RGS4 and RGS2 bind coatomer and inhibit COPI association with Golgi membranes and intracellular transport". Mol. Biol. Cell. 11 (9): 3155–68. doi:10.1091/mbc.11.9.3155. PMC   14982 . PMID   10982407.
22. Thaminy S, Auerbach D, Arnoldo A, Stagljar I (2003). "Identification of novel ErbB3-interacting factors using the split-ubiquitin membrane yeast two-hybrid system". Genome Res. 13 (7): 1744–53. doi:10.1101/gr.1276503. PMC   403748 . PMID   12840049.
23. Johnson EN, Seasholtz TM, Waheed AA, Kreutz B, Suzuki N, Kozasa T, Jones TL, Brown JH, Druey KM (December 2003). "RGS16 inhibits signalling through the G alpha 13-Rho axis". Nat. Cell Biol. 5 (12): 1095–103. doi:10.1038/ncb1065. PMID   14634662. S2CID   6798899.
24. Druey KM, Sullivan BM, Brown D, Fischer ER, Watson N, Blumer KJ, Gerfen CR, Scheschonka A, Kehrl JH (1998). "Expression of GTPase-deficient Gialpha2 results in translocation of cytoplasmic RGS4 to the plasma membrane". J. Biol. Chem. 273 (29): 18405–10. doi: 10.1074/jbc.273.29.18405 . PMID   9660808.

Further reading

• 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. doi: 10.1016/S0092-8674(00)80117-8 . PMID   8756726. S2CID   12427406.
• Levitt P, Ebert P, Mirnics K, et al. (2006). "Making the case for a candidate vulnerability gene in schizophrenia: Convergent evidence for regulator of G-protein signaling 4 (RGS4)". Biol. Psychiatry. 60 (6): 534–7. doi:10.1016/j.biopsych.2006.04.028. PMID   16860780. S2CID   3806917.
• Druey KM, Blumer KJ, Kang VH, Kehrl JH (1996). "Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family". Nature. 379 (6567): 742–6. Bibcode:1996Natur.379..742D. doi:10.1038/379742a0. PMID   8602223. S2CID   4362632.
• Heximer SP, Watson N, Linder ME, et al. (1998). "RGS2/G0S8 is a selective inhibitor of Gqalpha function". Proc. Natl. Acad. Sci. U.S.A. 94 (26): 14389–93. doi: 10.1073/pnas.94.26.14389 . PMC   24991 . PMID   9405622.
• Luo X, Popov S, Bera AK, Wilkie TM, Muallem S (March 2001). "RGS proteins provide biochemical control of agonist-evoked [Ca2+]i oscillations". Mol. Cell. 7 (3): 651–60. doi: 10.1016/S1097-2765(01)00211-8 . PMID   11463389.
• Pashkov V, Huang J, Parameswara VK, Kedzierski W, Kurrasch DM, Tall GG, Esser V, Gerard RD, Uyeda K, Towle HC, Wilkie TM (2011). "Regulator of G protein signaling (RGS16) inhibits hepatic fatty acid oxidation in a carbohydrate response element-binding protein (ChREBP)-dependent manner". J Biol Chem. 286 (17): 15116–15125. doi: 10.1074/jbc.M110.216234 . PMC   3083217 . PMID   21357625.
• Popov S, Yu K, Kozasa T, Wilkie TM (July 1997). "The regulators of G protein signaling (RGS) domains of RGS4, RGS10, and GAIP retain GTPase activating protein activity in vitro". Proc. Natl. Acad. Sci. U.S.A. 94 (14): 7216–20. Bibcode:1997PNAS...94.7216P. doi: 10.1073/pnas.94.14.7216 . PMC   23796 . PMID   9207071.
• Popov SG, Krishna UM, Falck JR, Wilkie TM (June 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. doi: 10.1074/jbc.M001128200 . PMID   10747990.
• Srinivasa SP, Bernstein LS, Blumer KJ, Linder ME (1998). "Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae". Proc. Natl. Acad. Sci. U.S.A. 95 (10): 5584–9. Bibcode:1998PNAS...95.5584S. doi: 10.1073/pnas.95.10.5584 . PMC   20421 . PMID   9576926.
• Druey KM, Sullivan BM, Brown D, et al. (1998). "Expression of GTPase-deficient Gialpha2 results in translocation of cytoplasmic RGS4 to the plasma membrane". J. Biol. Chem. 273 (29): 18405–10. doi: 10.1074/jbc.273.29.18405 . PMID   9660808.
• Faraone SV, Matise T, Svrakic D, et al. (1998). "Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium". Am. J. Med. Genet. 81 (4): 290–5. doi:10.1002/(SICI)1096-8628(19980710)81:4<290::AID-AJMG3>3.0.CO;2-Y. PMID   9674973.
• Wang J, Ducret A, Tu Y, et al. (1998). "RGSZ1, a Gz-selective RGS protein in brain. Structure, membrane association, regulation by Galphaz phosphorylation, and relationship to a Gz gtpase-activating protein subfamily". J. Biol. Chem. 273 (40): 26014–25. doi: 10.1074/jbc.273.40.26014 . PMID   9748280.
• Shaw SH, Kelly M, Smith AB, et al. (1998). "A genome-wide search for schizophrenia susceptibility genes". Am. J. Med. Genet. 81 (5): 364–76. doi:10.1002/(SICI)1096-8628(19980907)81:5<364::AID-AJMG4>3.0.CO;2-T. PMID   9754621.
• Posner BA, Mukhopadhyay S, Tesmer JJ, et al. (1999). "Modulation of the affinity and selectivity of RGS protein interaction with G alpha subunits by a conserved asparagine/serine residue". Biochemistry. 38 (24): 7773–9. doi:10.1021/bi9906367. PMID   10387017.
• Tu Y, Popov S, Slaughter C, Ross EM (2000). "Palmitoylation of a conserved cysteine in the regulator of G protein signaling (RGS) domain modulates the GTPase-activating activity of RGS4 and RGS10". J. Biol. Chem. 274 (53): 38260–7. doi: 10.1074/jbc.274.53.38260 . PMID   10608901.
• Moy FJ, Chanda PK, Cockett MI, et al. (2000). "1H, 15N, 13C, and 13CO assignments and secondary structure determination of RGS4". J. Biomol. NMR. 15 (4): 339–40. doi:10.1023/A:1008343609739. PMID   10685342. S2CID   37351864.
• 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. doi: 10.1074/jbc.M001128200 . PMID   10747990.
• Ekelund J, Lichtermann D, Hovatta I, et al. (2000). "Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22". Hum. Mol. Genet. 9 (7): 1049–57. doi: 10.1093/hmg/9.7.1049 . PMID   10767329.
• Brzustowicz LM, Hodgkinson KA, Chow EW, et al. (2000). "Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22". Science. 288 (5466): 678–82. Bibcode:2000Sci...288..678B. doi:10.1126/science.288.5466.678. PMC   3787922 . PMID   10784452.
• Chatterjee TK, Fisher RA (2000). "Cytoplasmic, nuclear, and golgi localization of RGS proteins. Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs". J. Biol. Chem. 275 (31): 24013–21. doi: 10.1074/jbc.M002082200 . PMID   10791963.
• Chatterjee TK, Fisher RA (2000). "Novel alternative splicing and nuclear localization of human RGS12 gene products". J. Biol. Chem. 275 (38): 29660–71. doi: 10.1074/jbc.M000330200 . PMID   10869340.
• Ross EM, Wilkie TM (2000). "GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins". Annual Review of Biochemistry. 69: 795–827. doi:10.1146/annurev.biochem.69.1.795. PMID   10966476. S2CID   11637673.
• Sierra DA, Gilbert DJ, Householder D, Grishin NV, Yu K, Ukidwe P, Barker SA, He W, Wensel TG, Otero G, Brown G, Copeland NG, Jenkins NA, Wilkie TM (2002). "Evolution of the regulators of G-protein signaling multigene family in mouse and human". Genomics. 79 (2): 177–85. doi:10.1006/geno.2002.6693. PMID   11829488. S2CID   16065132.
• Sullivan BM, Harrison-Lavoie KJ, Marshansky V, et al. (2000). "RGS4 and RGS2 bind coatomer and inhibit COPI association with Golgi membranes and intracellular transport". Mol. Biol. Cell. 11 (9): 3155–68. doi:10.1091/mbc.11.9.3155. PMC   14982 . PMID   10982407.
• Dowal L, Elliott J, Popov S, et al. (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. doi:10.1021/bi001923+. PMID   11148035.
• Richardson RM, Marjoram RJ, Barr AJ, Snyderman R (2001). "RGS4 inhibits platelet-activating factor receptor phosphorylation and cellular responses". Biochemistry. 40 (12): 3583–8. doi:10.1021/bi0019242. PMID   11297424.