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]
↑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. PMID8756726.
↑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. PMID19553869.
↑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. PMID19041089.
↑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. PMID18622782.
↑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. PMID15830230.
↑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. PMID16120478.
↑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. PMID19324084.
↑Jin Y, Zhong H, Omnaas JR, Neubig RR, Mosberg HI (2004). "Structure-based design, synthesis, and activity of peptide inhibitors of RGS4 GAP activity". Methods in Enzymology. 389: 266–77. doi:10.1016/S0076-6879(04)89016-5. PMID15313571.
↑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. PMID17012620.
↑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. PMID14634662.
↑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. PMID9660808.
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. PMID8756726.
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. PMID16860780.
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. doi:10.1038/379742a0. PMID8602223.
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. PMID11463389.
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. PMID9660808.
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. PMID9748280.
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. PMID10387017.
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. PMID10608901.
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. PMID10685342.
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. PMID10747990.
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. PMID10767329.
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. doi:10.1126/science.288.5466.678. PMID10784452.
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. PMID10791963.
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. PMID10869340.
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. PMID10966476.
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. PMID11829488.
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. PMID11148035.