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词条 RGS4
释义

  1. Function

  2. Clinical significance

  3. Inhibitors

  4. Interactions

  5. References

  6. Further reading

{{Infobox_gene}}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.[1]

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.[2] RGS proteins are able to deactivate G protein subunits of the Gi alpha, Go alpha and Gq 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.[3] 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.[1]

Clinical significance

A number of studies associate the RGS4 gene with schizophrenia,[4][5][6][7] while some fail to detect an association.[8]

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,[9] and may be important in the development of tolerance to opioid drugs.[10][11][12][13][14]

Inhibitors

  • cyclic peptides[15]
  • CCG-4986[16]

Interactions

RGS4 has been shown to interact with:

  • COPB2,[17]
  • ERBB3,[18] and
  • GNAQ.[19][20]

References

1. ^1 {{cite web | title = Entrez Gene: RGS4 regulator of G-protein signalling 4| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5999| accessdate = }}
2. ^{{cite journal |vauthors=Berman DM, Wilkie TM, Gilman AG |title=GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. |journal=Cell |volume=86 |issue= 3 |pages= 445–52 |year= 1996 |pmid= 8756726 |doi=10.1016/S0092-8674(00)80117-8 }}
3. ^{{cite journal |vauthors=Popov S, Yu K, Kozasa T, Wilkie TM | title = The regulators of G protein signaling (RGS) domains of RGS4, RGS10, and GAIP retain GTPase activating protein activity in vitro | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 14 | pages = 7216–20 |date=July 1997 | pmid = 9207071 | pmc = 23796 | doi = 10.1073/pnas.94.14.7216}}
4. ^{{cite journal |vauthors=Stefanis NC, Trikalinos TA, Avramopoulos D, Smyrnis N, Evdokimidis I, Ntzani EE, Hatzimanolis A, Ioannidis JP, Stefanis CN |title=Association of RGS4 variants with schizotypy and cognitive endophenotypes at the population level |journal=Behavioral and Brain Functions |volume=4 |pages=46 |year=2008 |pmid=18834502 |pmc=2572614 |doi=10.1186/1744-9081-4-46 |url=}}
5. ^{{cite journal |vauthors=Prasad KM, Almasy L, Gur RC, Gur RE, Pogue-Geile M, Chowdari KV, Talkowski ME, Nimgaonkar VL |title=RGS4 Polymorphisms Associated With Variability of Cognitive Performance in a Family-Based Schizophrenia Sample |journal=Schizophrenia Bulletin |volume= 36|issue= 5|pages= 983–90|date=March 2009 |pmid=19282471 |pmc=2930339 |doi=10.1093/schbul/sbp002 |url=}}
6. ^{{cite journal |vauthors=Dean B, Boer S, Gibbons A, Money T, Scarr E |title=Recent advances in postmortem pathology and neurochemistry in schizophrenia |journal=Current Opinion in Psychiatry |volume=22 |issue=2 |pages=154–60 |date=March 2009 |pmid=19553869 |doi=10.1097/YCO.0b013e328323d52e |url=}}
7. ^{{cite journal |vauthors=Ding L, Hegde AN |title=Expression of RGS4 splice variants in dorsolateral prefrontal cortex of schizophrenic and bipolar disorder patients |journal=Biological Psychiatry |volume=65 |issue=6 |pages=541–5 |date=March 2009 |pmid=19041089 |doi=10.1016/j.biopsych.2008.10.026 |url=}}
8. ^{{cite journal |vauthors=Stuart Gibbons A, Scarr E, McOmish CE, Hannan AJ, Thomas EA, Dean B |title=Regulator of G-protein signalling 4 expression is not altered in the prefrontal cortex in schizophrenia |journal=The Australian and New Zealand Journal of Psychiatry |volume=42 |issue=8 |pages=740–5 |date=August 2008 |pmid=18622782 |doi=10.1080/00048670802206338 |url=}}
9. ^{{cite journal |vauthors=Hooks SB, Martemyanov K, Zachariou V |title=A role of RGS proteins in drug addiction |journal=Biochemical Pharmacology |volume=75 |issue=1 |pages=76–84 |date=January 2008 |pmid=17880927 |doi=10.1016/j.bcp.2007.07.045 |url=}}
10. ^{{cite journal |vauthors=Grillet N, Pattyn A, Contet C, Kieffer BL, Goridis C, Brunet JF |title=Generation and characterization of Rgs4 mutant mice |journal=Molecular and Cellular Biology |volume=25 |issue=10 |pages=4221–8 |date=May 2005 |pmid=15870291 |pmc=1087729 |doi=10.1128/MCB.25.10.4221-4228.2005 |url=}}
11. ^{{cite journal |vauthors=Garzón J, Rodríguez-Muñoz M, de la Torre-Madrid E, Sánchez-Blázquez P |title=Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid receptors in the CNS |journal=Psychopharmacology |volume=180 |issue=1 |pages=1–11 |date=June 2005 |pmid=15830230 |doi=10.1007/s00213-005-2248-9 |url=}}
12. ^{{cite journal |vauthors=Georgoussi Z, Leontiadis L, Mazarakou G, Merkouris M, Hyde K, Hamm H |title=Selective interactions between G protein subunits and RGS4 with the C-terminal domains of the mu- and delta-opioid receptors regulate opioid receptor signaling |journal=Cellular Signalling |volume=18 |issue=6 |pages=771–82 |date=June 2006 |pmid=16120478 |doi=10.1016/j.cellsig.2005.07.003 |url=}}
13. ^{{cite journal |vauthors=Leontiadis LJ, Papakonstantinou MP, Georgoussi Z |title=Regulator of G protein signaling 4 confers selectivity to specific G proteins to modulate mu- and delta-opioid receptor signaling |journal=Cellular Signalling |volume=21 |issue=7 |pages=1218–28 |date=July 2009 |pmid=19324084 |doi=10.1016/j.cellsig.2009.03.013 |url=}}
14. ^{{cite journal |vauthors=Wang Q, Liu-Chen LY, Traynor JR |title=Differential Modulation of {micro}- and {delta}-Opioid Receptor Agonists by Endogenous RGS4 Protein in SH-SY5Y Cells |journal=The Journal of Biological Chemistry |volume=284 |issue=27 |pages=18357–67 |date=July 2009 |pmid=19416973 |doi=10.1074/jbc.M109.015453 |url= |pmc=2709384}}
15. ^{{cite journal |vauthors=Jin Y, Zhong H, Omnaas JR, Neubig RR, Mosberg HI |title=Structure-based design, synthesis, and activity of peptide inhibitors of RGS4 GAP activity |journal=Methods in Enzymology |volume=389 |issue= |pages=266–77 |year=2004 |pmid=15313571 |doi=10.1016/S0076-6879(04)89016-5 |url=}}
16. ^{{cite journal |vauthors=Roman DL, Talbot JN, Roof RA, Sunahara RK, Traynor JR, Neubig RR |title=Identification of small-molecule inhibitors of RGS4 using a high-throughput flow cytometry protein interaction assay |journal=Molecular Pharmacology |volume=71 |issue=1 |pages=169–75 |date=January 2007 |pmid=17012620 |doi=10.1124/mol.106.028670 |url= |issn=}}
17. ^{{cite journal |vauthors=Sullivan BM, Harrison-Lavoie KJ, Marshansky V, Lin HY, Kehrl JH, Ausiello DA, Brown D, Druey KM | title = RGS4 and RGS2 bind coatomer and inhibit COPI association with Golgi membranes and intracellular transport | journal = Mol. Biol. Cell | volume = 11 | issue = 9 | pages = 3155–68 | year = 2000 | pmid = 10982407 | pmc = 14982 | doi = 10.1091/mbc.11.9.3155}}
18. ^{{cite journal |vauthors=Thaminy S, Auerbach D, Arnoldo A, Stagljar I | title = Identification of novel ErbB3-interacting factors using the split-ubiquitin membrane yeast two-hybrid system | journal = Genome Res. | volume = 13 | issue = 7 | pages = 1744–53 | year = 2003 | pmid = 12840049 | pmc = 403748 | doi = 10.1101/gr.1276503 }}
19. ^{{cite journal |vauthors=Johnson EN, Seasholtz TM, Waheed AA, Kreutz B, Suzuki N, Kozasa T, Jones TL, Brown JH, Druey KM | title = RGS16 inhibits signalling through the G alpha 13-Rho axis | journal = Nat. Cell Biol. | volume = 5 | issue = 12 | pages = 1095–103 |date=December 2003 | pmid = 14634662 | doi = 10.1038/ncb1065 }}
20. ^{{cite journal |vauthors=Druey KM, Sullivan BM, Brown D, Fischer ER, Watson N, Blumer KJ, Gerfen CR, Scheschonka A, Kehrl JH | title = Expression of GTPase-deficient Gialpha2 results in translocation of cytoplasmic RGS4 to the plasma membrane | journal = J. Biol. Chem. | volume = 273 | issue = 29 | pages = 18405–10 | year = 1998 | pmid = 9660808 | doi = 10.1074/jbc.273.29.18405}}

Further reading

{{refbegin|35em}}
  • {{cite journal |vauthors=Berman DM, Wilkie TM, Gilman AG |title=GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. |journal=Cell |volume=86 |issue= 3 |pages= 445–52 |year= 1996 |pmid= 8756726 |doi=10.1016/S0092-8674(00)80117-8 }}
  • {{cite journal |vauthors=Levitt P, Ebert P, Mirnics K, etal |title=Making the case for a candidate vulnerability gene in schizophrenia: Convergent evidence for regulator of G-protein signaling 4 (RGS4). |journal=Biol. Psychiatry |volume=60 |issue= 6 |pages= 534–7 |year= 2006 |pmid= 16860780 |doi= 10.1016/j.biopsych.2006.04.028 }}
  • {{cite journal |vauthors=Druey KM, Blumer KJ, Kang VH, Kehrl JH |title=Inhibition of G-protein-mediated MAP kinase activation by a new mammalian gene family. |journal=Nature |volume=379 |issue= 6567 |pages= 742–6 |year= 1996 |pmid= 8602223 |doi= 10.1038/379742a0 }}
  • {{cite journal |vauthors=Heximer SP, Watson N, Linder ME, etal |title=RGS2/G0S8 is a selective inhibitor of Gqalpha function. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 26 |pages= 14389–93 |year= 1998 |pmid= 9405622 |doi=10.1073/pnas.94.26.14389 | pmc=24991 }}
  • {{cite journal |vauthors=Luo X, Popov S, Bera AK, Wilkie TM, Muallem S | title = RGS proteins provide biochemical control of agonist-evoked [Ca2+]i oscillations | journal = Mol. Cell | volume = 7 | issue = 3 | pages = 651–60 |date=March 2001 | pmid = 11463389 | doi = 10.1016/S1097-2765(01)00211-8}}
  • {{cite journal |vauthors=Pashkov V, Huang J, Parameswara VK, Kedzierski W, Kurrasch DM, Tall GG, Esser V, Gerard RD, Uyeda K, Towle HC, Wilkie TM |title=Regulator of G protein signaling (RGS16) inhibits hepatic fatty acid oxidation in a carbohydrate response element-binding protein (ChREBP)-dependent manner |journal=J Biol Chem |volume=286 |issue=17 |pages=15116–15125 |year=2011 |pmid=21357625 |doi=10.1074/jbc.M110.216234 |pmc=3083217}}
  • {{cite journal |vauthors=Popov S, Yu K, Kozasa T, Wilkie TM | title = The regulators of G protein signaling (RGS) domains of RGS4, RGS10, and GAIP retain GTPase activating protein activity in vitro | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 94 | issue = 14 | pages = 7216–20 |date=July 1997 | pmid = 9207071 | pmc = 23796 | doi = 10.1073/pnas.94.14.7216}}
  • {{cite journal |vauthors=Popov SG, Krishna UM, Falck JR, Wilkie TM | title = Ca2+/Calmodulin reverses phosphatidylinositol 3,4, 5-trisphosphate-dependent inhibition of regulators of G protein-signaling GTPase-activating protein activity | journal = J. Biol. Chem. | volume = 275 | issue = 25 | pages = 18962–8 |date=June 2000 | pmid = 10747990 | doi = 10.1074/jbc.M001128200 | url = }}
  • {{cite journal |vauthors=Srinivasa SP, Bernstein LS, Blumer KJ, Linder ME |title=Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=95 |issue= 10 |pages= 5584–9 |year= 1998 |pmid= 9576926 |doi=10.1073/pnas.95.10.5584 | pmc=20421 }}
  • {{cite journal |vauthors=Druey KM, Sullivan BM, Brown D, etal |title=Expression of GTPase-deficient Gialpha2 results in translocation of cytoplasmic RGS4 to the plasma membrane. |journal=J. Biol. Chem. |volume=273 |issue= 29 |pages= 18405–10 |year= 1998 |pmid= 9660808 |doi=10.1074/jbc.273.29.18405 }}
  • {{cite journal |vauthors=Faraone SV, Matise T, Svrakic D, etal |title=Genome scan of European-American schizophrenia pedigrees: results of the NIMH Genetics Initiative and Millennium Consortium. |journal=Am. J. Med. Genet. |volume=81 |issue= 4 |pages= 290–5 |year= 1998 |pmid= 9674973 |doi=10.1002/(SICI)1096-8628(19980710)81:4<290::AID-AJMG3>3.0.CO;2-Y }}
  • {{cite journal |vauthors=Wang J, Ducret A, Tu Y, etal |title=RGSZ1, a Gz-selective RGS protein in brain. Structure, membrane association, regulation by Galphaz phosphorylation, and relationship to a Gz gtpase-activating protein subfamily. |journal=J. Biol. Chem. |volume=273 |issue= 40 |pages= 26014–25 |year= 1998 |pmid= 9748280 |doi=10.1074/jbc.273.40.26014 }}
  • {{cite journal |vauthors=Shaw SH, Kelly M, Smith AB, etal |title=A genome-wide search for schizophrenia susceptibility genes. |journal=Am. J. Med. Genet. |volume=81 |issue= 5 |pages= 364–76 |year= 1998 |pmid= 9754621 |doi=10.1002/(SICI)1096-8628(19980907)81:5<364::AID-AJMG4>3.0.CO;2-T }}
  • {{cite journal |vauthors=Posner BA, Mukhopadhyay S, Tesmer JJ, etal |title=Modulation of the affinity and selectivity of RGS protein interaction with G alpha subunits by a conserved asparagine/serine residue. |journal=Biochemistry |volume=38 |issue= 24 |pages= 7773–9 |year= 1999 |pmid= 10387017 |doi= 10.1021/bi9906367 }}
  • {{cite journal |vauthors=Tu Y, Popov S, Slaughter C, Ross EM |title=Palmitoylation of a conserved cysteine in the regulator of G protein signaling (RGS) domain modulates the GTPase-activating activity of RGS4 and RGS10. |journal=J. Biol. Chem. |volume=274 |issue= 53 |pages= 38260–7 |year= 2000 |pmid= 10608901 |doi=10.1074/jbc.274.53.38260 }}
  • {{cite journal |vauthors=Moy FJ, Chanda PK, Cockett MI, etal |title=1H, 15N, 13C, and 13CO assignments and secondary structure determination of RGS4. |journal=J. Biomol. NMR |volume=15 |issue= 4 |pages= 339–40 |year= 2000 |pmid= 10685342 |doi=10.1023/A:1008343609739 }}
  • {{cite journal |vauthors=Popov SG, Krishna UM, Falck JR, Wilkie TM |title=Ca2+/Calmodulin reverses phosphatidylinositol 3,4, 5-trisphosphate-dependent inhibition of regulators of G protein-signaling GTPase-activating protein activity. |journal=J. Biol. Chem. |volume=275 |issue= 25 |pages= 18962–8 |year= 2000 |pmid= 10747990 |doi= 10.1074/jbc.M001128200 }}
  • {{cite journal |vauthors=Ekelund J, Lichtermann D, Hovatta I, etal |title=Genome-wide scan for schizophrenia in the Finnish population: evidence for a locus on chromosome 7q22. |journal=Hum. Mol. Genet. |volume=9 |issue= 7 |pages= 1049–57 |year= 2000 |pmid= 10767329 |doi=10.1093/hmg/9.7.1049 }}
  • {{cite journal |vauthors=Brzustowicz LM, Hodgkinson KA, Chow EW, etal |title=Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22. |journal=Science |volume=288 |issue= 5466 |pages= 678–82 |year= 2000 |pmid= 10784452 |doi=10.1126/science.288.5466.678 |pmc=3787922 }}
  • {{cite journal |vauthors=Chatterjee TK, Fisher RA |title=Cytoplasmic, nuclear, and golgi localization of RGS proteins. Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs. |journal=J. Biol. Chem. |volume=275 |issue= 31 |pages= 24013–21 |year= 2000 |pmid= 10791963 |doi= 10.1074/jbc.M002082200 }}
  • {{cite journal |vauthors=Chatterjee TK, Fisher RA |title=Novel alternative splicing and nuclear localization of human RGS12 gene products. |journal=J. Biol. Chem. |volume=275 |issue= 38 |pages= 29660–71 |year= 2000 |pmid= 10869340 |doi= 10.1074/jbc.M000330200 }}
  • {{cite journal |vauthors=Ross EM, Wilkie TM |title=GTPase-activating proteins for heterotrimeric G proteins: regulators of G protein signaling (RGS) and RGS-like proteins |journal=Annual Review of Biochemistry |volume=69 |pages=795–827 |year= 2000 |pmid= 10966476 |doi=10.1146/annurev.biochem.69.1.795}}
  • {{cite journal |vauthors=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 |title=Evolution of the regulators of G-protein signaling multigene family in mouse and human |journal=Genomics |volume=79 |issue= 2 |pages= 177–85 |year= 2002 |pmid= 11829488 |doi= 10.1006/geno.2002.6693 }}
  • {{cite journal |vauthors=Sullivan BM, Harrison-Lavoie KJ, Marshansky V, etal |title=RGS4 and RGS2 bind coatomer and inhibit COPI association with Golgi membranes and intracellular transport. |journal=Mol. Biol. Cell |volume=11 |issue= 9 |pages= 3155–68 |year= 2000 |pmid= 10982407 |doi= 10.1091/mbc.11.9.3155| pmc=14982 }}
  • {{cite journal |vauthors=Dowal L, Elliott J, Popov S, etal |title=Determination of the contact energies between a regulator of G protein signaling and G protein subunits and phospholipase C beta 1. |journal=Biochemistry |volume=40 |issue= 2 |pages= 414–21 |year= 2001 |pmid= 11148035 |doi=10.1021/bi001923 }}
  • {{cite journal |vauthors=Richardson RM, Marjoram RJ, Barr AJ, Snyderman R |title=RGS4 inhibits platelet-activating factor receptor phosphorylation and cellular responses. |journal=Biochemistry |volume=40 |issue= 12 |pages= 3583–8 |year= 2001 |pmid= 11297424 |doi=10.1021/bi0019242 }}
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