Past and Future Strategies for GPCR Deorphanization

GPCR Molecular Pharmacology and Drug Targeting: Shifting Paradigms and New Directions

Volumn , Issue , 2010, Pages 165-190

  Levoye, Angélique ^a,b   Clement, Nathalie ^b,c   Tenconi, Elodie ^b,c   Jockers, Ralf ^b,c  

^a INSTITUT PASTEUR   (France)

^b INSERM   (France)

^c INSTITUT COCHIN   (France)

Author keywords

7TM protein deorphanization, being difficult and new screening strategies helping to deorphanize further orphans; Functional assays for deorphanization; GPCR deorphanization, past and future strategies seven transmembrane (7TM) domain GPCRs, largest membrane receptor family

Indexed keywords

EID: 84884952646     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9780470627327.ch7     Document Type: Chapter

References (121)

1. Bockaert, J., Pin, J.P. (1999) Molecular tinkering of G protein-coupled receptors: An evolutionary success. EMBO J. 18, 1723-1729.
2. Drews, J. (2000) Drug discovery: A historical perspective. Science. 287, 1960-1964.
3. Fredriksson, R., Lagerstrom, M.C., Lundin, L.G., Schioth, H.B. (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol. 63, 1256-1272.
4. Joost, P., Methner, A. (2002) Phylogenetic analysis of 277 human G-protein - coupled receptors as a tool for the prediction of orphan receptor ligands. Genome Biol. 3, RESEARCH0063.
5. Vassilatis, D.K., Hohmann, J.G., Zeng, H., Li, F., Ranchalis, J.E., Mortrud, M.T., Brown, A., Rodriguez, S.S., Weller, J.R., Wright, A.C., Bergmann, J.E., Gaitanaris, G.A. (2003) The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci U S A. 100, 4903-4908.
6. Civelli, O. (2005) GPCR deorphanizations: The novel, the known and the unexpected transmitters. Trends Pharmacol Sci. 26, 15-19.
7. Dixon, R.A.F., Kobilka, B.K., Strader, D.J., Benovic, J.L., Dohlman, H.G., Frielle, T., Bolanowski, M.A., Bennett, C.D., Rands, E., Diehl, R.E., Mumford, R.A., Slater, E.E., Sigal, I.S., Caron, M.G., Lefkowitz, R.J., Strader, C.D. (1986) Cloning of the gene and cDNA for mammalian ß-adrenergic receptor and homology with rhodopsin. Nature. 321, 75-79.
8. Bunzow, J.R., Van Tol, H.H., Grandy, D.K., Albert, P., Salon, J., Christie, M., Machida, C.A., Neve, K.A., Civelli, O. (1988) Cloning and expression of a rat D2 dopamine receptor cDNA. Nature. 336, 783-787.
9. Libert, F., Parmentier, M., Lefort, A., Dinsart, C., Van Sande, J., Maenhaut, C., Simons, M.-J., Dumont, J.E., Vassart, G. (1989) Selective amplification and cloning of four new members of the G protein-coupled receptor family. Science. 244, 569-572.
10. O' Dowd, B.F., Nguyen, T., Jung, B.P., Marchese, A., Cheng, R., Heng, H.H., Kolakowski Jr., L.F., Lynch, K.R., George, S.R. (1997) Cloning and chromosomal mapping of four putative novel human G-protein-coupled receptor genes. Gene. 187, 75-81.
11. Civelli, O., Nothacker, H.P., Saito, Y., Wang, Z., Lin, S.H., Reinscheid, R.K. (2001) Novel neurotransmitters as natural ligands of orphan G-protein-coupled receptors . Trends Neurosci. 24, 230-237.
12. Reinscheid, R.K., Nothacker, H.P., Bourson, A., Ardati, A., Henningsen, R.A., Bunzow, J.R., Grandy, D.K., Langen, H., Monsma Jr., F.J., Civelli, O. (1995) Orphanin FQ: A neuropeptide that activates an opioidlike G protein-coupled receptor. Science 270, 792-794.
13. Fargin, A., Raymond, J.R., Lohse, M.J., Kobilka, B.K., Caron, M.G., Lefkowitz, R.J. (1988) The genomic clone G-21 which resembles a ß-adrenergic receptor sequence encodes the 5HT1A receptor. Nature. 335, 358-360.
14. Libert, F., Schiffmann, S.N., Lefort, A., Parmentier, M., Gerard, C., Dumont, J.E., Vanderhaeghen, J.J., Vassart, G. (1991) The orphan receptor cDNA RDC7 encodes an A1 adenosine receptor. EMBO J. 10, 1677-82.
15. Libert, F., Vassart, G., Parmentier, M. (1991) Current developments in G-protein - coupled receptors. Curr Opin Cell Biol. 3, 218-223.
16. Mills, A., Duggan, M.J. (1994) Orphan seven transmembrane domain receptors: Reversing pharmacology. Trends Biotechnol. 12, 47-49.
17. Wang, J., Simonavicius, N., Wu, X., Swaminath, G., Reagan, J., Tian, H., Ling, L. (2006) Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J Biol Chem. 281, 22021-2208.
18. Wang, J., Wu, X., Simonavicius, N., Tian, H., Ling, L. (2006) Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J Biol Chem. 281, 34457-34464.
19. Ignatov, A., Robert, J., Gregory-Evans, C., Schaller, H.C. (2006) RANTES stimulates Ca2+ mobilization and inositol trisphosphate (IP3) formation in cells transfected with G protein-coupled receptor 75. Br J Pharmacol. 149, 490-497.
20. Henderson, G., McKnight, A.T. (1997) The orphan opioid receptor and its endogenous ligand - nociceptin/orphanin FQ. Trends Pharmacol Sci. 18, 293-300.
21. Meunier, J.C., Mollereau, C., Toll, L., Suaudeau, C., Moisand, C., Alvinerie, P., Butour, J.L., Guillemot, J.C., Ferrara, P., Monsarrat, B., Mazarguil, H., Vassart, G., Parmentier, M., Costentin, J. (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature. 377, 532-535.
22. Wise, A., Jupe, S.C., Rees, S. (2004) The identification of ligands at orphan G-protein coupled receptors. Annu Rev Pharmacol Toxicol. 44, 43-66.
23. Civelli, O., Saito, Y., Wang, Z., Nothacker, H.P., Reinscheid, R.K. (2006) Orphan GPCRs and their ligands. Pharmacol Ther. 110, 525-532.
24. Jacoby, E. (2006) Chemogenomics: Drug discovery' s panacea? Mol Biosyst. 2, 218-220.
25. Metpally, R.P., Sowdhamini, R. (2005) Cross genome phylogenetic analysis of human and Drosophila G protein-coupled receptors: Application to functional annotation of orphan receptors. BMC Genomics. 6, 106.
26. Fredriksson, R., Schioth, H.B. (2005) The repertoire of G-protein-coupled receptors in fully sequenced genomes. Mol Pharmacol. 67, 1414-1425.
27. Murakami, M., Shiraishi, A., Tabata, K., Fujita, N. (2008) Identification of the orphan GPCR, P2Y(10) receptor as the sphingosine-1-phosphate and lysophosphatidic acid receptor. Biochem Biophys Res Commun. 371, 707-712.
28. Ciana, P., Fumagalli, M., Trincavelli, M.L., Verderio, C., Rosa, P., Lecca, D., Ferrario, S., Parravicini, C., Capra, V., Gelosa, P., Guerrini, U., Belcredito, S., Cimino, M., Sironi, L., Tremoli, E., Rovati, G.E., Martini, C., Abbracchio, M.P. (2006) The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl - leukotrienes receptor. EMBO J. 25, 4615-4627.
29. Surgand, J.S., Rodrigo, J., Kellenberger, E., Rognan, D. (2006) A chemogenomic analysis of the transmembrane binding cavity of human G-protein-coupled receptors . Proteins. 62, 509-538.
30. Wellendorph, P., Hansen, K.B., Balsgaard, A., Greenwood, J.R., Egebjerg, J., Brauner-Osborne, H. (2005) Deorphanization of GPRC6A: A promiscuous L-alpha-amino acid receptor with preference for basic amino acids. Mol Pharmacol. 67, 589-597.
31. Tunaru, S., Kero, J., Schaub, A., Wufka, C., Blaukat, A., Pfeffer, K., Offermanns, S. (2003) PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti - lipolytic effect. Nat Med. 9, 352-355.
32. Morita, H., Mazerbourg, S., Bouley, D.M., Luo, C.W., Kawamura, K., Kuwabara, Y., Baribault, H., Tian, H., Hsueh, A.J. (2004) Neonatal lethality of LGR5 null mice is associated with ankyloglossia and gastrointestinal distension. Mol Cell Biol. 24, 9736-9743.
33. Matteson, P.G., Desai, J., Korstanje, R., Lazar, G., Borsuk, T.E., Rollins, J., Kadambi, S., Joseph, J., Rahman, T., Wink, J., Benayed, R., Paigen, B., Millonig, J.H. (2008) The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development. Proc Natl Acad Sci U S A. 105, 2088-2093.
34. Ivanova, E.A., Bechtold, D., Dupre, S., Brennand, J., Barrett, P., Luckman, S., Loudon A.S. (2008) Altered metabolism in the melatonin-related receptor (GPR50) knock out mouse. Am J Physiol Endocrinol Metab. 294, E176-E182.
35. Cox, P.J., Pitcher, T., Trim, S.A., Bell, C.H., Qin, W., Kinloch, R.A. (2008) The effect of deletion of the orphan G-protein coupled receptor (GPCR) gene MrgE on pain-like behaviours in mice. Mol Pain. 4, 2.
36. Matsumoto, M., Straub, R.E., Marenco, S., Nicodemus, K.K., Matsumoto, S., Fujikawa, A., Miyoshi, S., Shobo, M., Takahashi, S., Yarimizu, J., Yuri, M., Hiramoto, M., Morita, S., Yokota, H., Sasayama, T., Terai, K., Yoshino, M., Miyake, A., Callicott, J.H., Egan, M.F., Meyer-Lindenberg, A., Kempf, L., Honea, R., Vakkalanka, R.K., Takasaki, J., Kamohara, M., Soga, T., Hiyama, H., Ishii, H., Matsuo, A., Nishimura, S., Matsuoka, N., Kobori, M., Matsushime, H., Katoh, M., Furuichi, K., Weinberger, D.R. (2008) The evolutionarily conserved G protein-coupled receptor SREB2/ GPR85 influences brain size, behavior, and vulnerability to schizophrenia. Proc Natl Acad Sci U S A. 105, 6133-6138.
37. Eglen, R.M., Bosse, R., Reisine, T. (2007) Emerging concepts of guanine nucleotide - binding protein-coupled receptor (GPCR) function and implications for high throughput screening. Assay Drug Dev Technol. 5, 425-451.
38. Johnson, E.N., Shi, X., Cassaday, J., Ferrer, M., Strulovici, B., Kunapuli, P. (2008) A 1,536-well [(35)S]GTPgammaS scintillation proximity binding assay for ultra - high-throughput screening of an orphan galphai-coupled GPCR. Assay Drug Dev Technol. 6, 327-637.
39. Potenza, M.N., Graminski, G.F., Lerner, M.R. (1992) A method for evaluating the effects of ligands upon Gs protein-coupled receptors using a recombinant melanophore - based bioassay. Anal Biochem. 206, 315-322.
40. Ames, R.S., Li, Y., Sarau, H.M., Nuthulaganti, P., Foley, J.J., Ellis, C., Zeng, Z., Su, K., Jurewicz, A.J., Hertzberg, R.P., Bergsma, D.J., Kumar, C. (1996) Molecular cloning and characterization of the human anaphylatoxin C3a receptor. J Biol Chem. 271, 20231-20234.
41. Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., Kangawa, K. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 402, 656-660.
42. Schaeffer, M.T., Cully, D., Chou, M., Liu, J., Van der Ploeg, L.H., Fong, T.M. (1999) Use of bioluminescent aequorin for the pharmacological characterization of 5HT receptors. J Recept Signal Transduct Res. 19, 927-938.
43. Coward, P., Chan, S.D., Wada, H.G., Humphries, G.M., Conklin, B.R. (1999) Chimeric G proteins allow a high-throughput signaling assay of Gi-coupled receptors . Anal Biochem. 270, 242-248.
44. Offermanns, S., Simon, M.I. (1995) Ga15 and Ga16 couple a wide variety of receptors to phospholipase C. J Biol Chem. 270, 15175-15180.
45. Lefkowitz, R.J., Shenoy, S.K. (2005) Transduction of receptor signals by beta - arrestins. Science. 308, 512-517.
46. Cain, S.A., Monk, P.N. (2002) The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg(74). J Biol Chem. 277, 7165-7169.
47. Kalant, D., Cain, S.A., Maslowska, M., Sniderman, A.D., Cianflone, K., Monk, P.N. (2003) The chemoattractant receptor-like protein C5L2 binds the C3a des-Arg77/ acylation-stimulating protein. J Biol Chem. 278, 11123-11129.
48. Mantovani, A., Locati, M., Vecchi, A., Sozzani, S., Allavena, P. (2001) Decoy receptors: A strategy to regulate inflammatory cytokines and chemokines. Trends Immunol. 22, 328-336.
49. Bertin, B., Freissmuth, M., Jockers, R., Strosberg, A.D., Marullo, S. (1994) Cellular signaling by an agonist-activated receptor/G(s)alpha fusion protein. Proc Natl Acad Sci U S A. 91, 8827-8831.
50. Guo, Z.D., Suga, H., Okamura, M., Takeda, S., Haga, T. (2001) Receptor-Galpha fusion proteins as a tool for ligand screening. Life Sci. 68, 2319-2327.
51. Suga, H., Haga, T. (2007) Ligand screening system using fusion proteins of G protein - coupled receptors with G protein alpha subunits. Neurochem Int. 51, 140-164.
52. Takeda, S., Yamamoto, A., Okada, T., Matsumura, E., Nose, E., Kogure, K., Kojima, S., Haga, T. (2003) Identification of surrogate ligands for orphan G protein-coupled receptors. Life Sci. 74, 367-377.
53. Takeda, S., Kadowaki, S., Haga, T., Takaesu, H., Mitaku, S. (2002) Identification of G protein-coupled receptor genes from the human genome sequence. FEBS Lett. 520, 97-101.
54. Hosoi, T., Koguchi, Y., Sugikawa, E., Chikada, A., Ogawa, K., Tsuda, N., Suto, N., Tsunoda, S., Taniguchi, T., Ohnuki, T. (2002) Identification of a novel human eicosanoid receptor coupled to G(i/o). J Biol Chem. 277, 31459-31465.
55. Tabata, K., Baba, K., Shiraishi, A., Ito, M., Fujita, N. (2007) The orphan GPCR GPR87 was deorphanized and shown to be a lysophosphatidic acid receptor. Biochem Biophys Res Commun. 363, 861-866.
56. Hirasawa, A., Tsumaya, K., Awaji, T., Katsuma, S., Adachi, T., Yamada, M., Sugimoto, Y., Miyazaki, S., Tsujimoto, G. (2005) Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nat Med. 11, 90-94.
57. Crouch, M.F., Osmond, R.I. (2008) New strategies in drug discovery for GPCRs: High throughput detection of cellular ERK phosphorylation. Comb Chem High Throughput Screen. 11, 344-356.
58. Jockers, R., Da Silva, A., Strosberg, A.D., Bouvier, M., Marullo, S. (1996) New molecular and structural determinants involved in ß 2-adrenergic receptor desensitization and sequestration; delineation using chimeric ß 3/ ß 2-adrenergic receptors . J Biol Chem. 271, 9355-9362.
59. Adie, E.J., Francis, M.J., Davies, J., Smith, L., Marenghi, A., Hather, C., Hadingham, K., Michael, N.P., Milligan, G., Game, S. (2003) CypHer 5: A generic approach for measuring the activation and trafficking of G protein-coupled receptors in live cells. Assay Drug Dev Technol. 1, 251-259.
60. Beletskii, A., Cooper, M., Sriraman, P., Chiriac, C., Zhao, L., Abbot, S., Yu, L. (2005) High-throughput phagocytosis assay utilizing a pH-sensitive fluorescent dye. Biotechniques. 39, 894-897.
61. Oakley, R.H., Hudson, C.C., Sjaastad, M.D., Loomis, C.R. (2006) The ligand-independent translocation assay: An enabling technology for screening orphan G protein-coupled receptors by arrestin recruitment. Methods Enzymol. 414, 50-63.
62. Fergusson, S.S., Caron, M.G. (2004) Green fluorescent protein-tagged ß-arrestin translocation as a measure of G protein-coupled receptor activation. Methods Mol Biol. 237, 121-126.
63. Johnson, E.C., Bohn, L.M., Barak, L.S., Birse, R.T., Nassel, D.R., Caron, M.G., Taghert, P.H. (2003) Identification of Drosophila neuropeptide receptors by G protein- coupled receptors- beta- arrestin2 interactions. J Biol Chem. 278, 52172-52178.
64. Kalant, D., MacLaren, R., Cui, W., Samanta, R., Monk, P.N., Laporte, S.A., Cianflone, K. (2005) C5L2 is a functional receptor for acylation-stimulating protein. J Biol Chem. 280, 23936-23944.
65. Bertrand, L., Parent, S., Caron, M., Legault, M., Joly, E., Angers, S., Bouvier, M., Brown, M., Houle, B., Menard, L. (2002) The BRET2/arrestin assay in stable recombinant cells: A platform to screen for compounds that interact with G protein-coupled receptors (GPCRS). J Recept Signal Transduct Res. 22, 533-541.
66. Heding, A. (2004) Use of the BRET 7TM receptor/beta-arrestin assay in drug discovery and screening. Expert Rev Mol Diagn. 4, 403-411.
67. Vrecl, M., Jorgensen, R., Pogacnik, A., Heding, A. (2004) Development of a BRET2 screening assay using beta-arrestin 2 mutants. J Biomol Screen. 9, 322-333.
68. Verkaar, F., van Rosmalen, J.W., Blomenrohr, M., van Koppen, C.J., Blankesteijn, W.M., Smits, J.F., Zaman, G.J. (2008) G protein-independent cell-based assays for drug discovery on seven-transmembrane receptors. Biotechnol Annu Rev. 14, 253-274.
69. Barnea, G., Strapps, W., Herrada, G., Berman, Y., Ong, J., Kloss, B., Axel, R., Lee, K.J. (2008) The genetic design of signaling cascades to record receptor activation. Proc Natl Acad Sci U S A. 105, 64-69.
70. Olson, K.R., Eglen, R.M. (2007) Beta galactosidase complementation: A cell - based luminescent assay platform for drug discovery. Assay Drug Dev Technol. 5, 137-144.
71. Carman, C.V., Som, T., Kim, C.M., Benovic, J.L. (1998) Binding and phosphorylation of tubulin by G protein-coupled receptor kinases. J Biol Chem. 273, 20308-20316.
72. Pierce, K.L., Lefkowitz, R.J. (2001) Classical and new roles of beta-arrestins in the regulation of G-protein-coupled receptors. Nat Rev Neurosci. 2, 727-733.
73. Levoye, A., Jockers, R. (2008) Alternative drug discovery approaches for orphan GPCRs. Drug Discov Today. 13, 52-58.
74. Kaupmann, K., Malitschek, B., Schuler, V., Heid, J., Froestl, W., Beck, P., Mosbacher, J., Bischoff, S., Kulik, A., Shigemoto, R., Karschin, A., Bettler, B. (1998) GABA(B) - receptor subtypes assemble into functional heteromeric complexes. Nature. 396, 683-687.
75. White, J.H., Wise, A., Main, M.J., Green, A., Fraser, N.J., Disney, G.H., Barnes, A.A., Emson, P., Foord, S.M., Marshall, F.H. (1998) Heterodimerization is required for the formation of a functional GABA(B) receptor. Nature. 396, 679-682.
76. Jones, K.A., Borowsky, B., Tamm, J.A., Gerald, C. (1998) GABAb receptors function as a heterotrimeric assembly of the subunits GABAbR1 and GAGbR2. Nature. 396, 674-679.
77. Pin, J.P., Kniazeff, J., Liu, J., Binet, V., Goudet, C., Rondard, P., Prezeau, L. (2005) Allosteric functioning of dimeric class C G-protein-coupled receptors. FEBS J. 272, 2947-2955.
78. Nelson, G., Hoon, M.A., Chandrashekar, J., Zhang, Y., Ryba, N.J., Zuker, C.S. (2001) Mammalian sweet taste receptors. Cell. 106, 381-390.
79. Nelson, G., Chandrashekar, J., Hoon, M.A., Feng, L., Zhao, G., Ryba, N.J., Zuker, C.S. (2002) An amino-acid taste receptor. Nature. 416, 199-202.
80. Xu, H., Staszewski, L., Tang, H., Adler, E., Zoller, M., Li, X. (2004) Different functional roles of T1R subunits in the heteromeric taste receptors. Proc Natl Acad Sci U S A. 101, 14258-14263.
81. Levoye, A., Dam, J., Ayoub, M.A., Guillaume, J.L., Couturier, C., Delagrange, P., Jockers, R. (2006) The orphan GPR50 receptor specifically inhibits MT(1) melatonin receptor function through heterodimerization. EMBO J. 25, 3012-3023.
82. Milasta, S., Pediani, J., Appelbe, S., Trim, S., Wyatt, M., Cox, P., Fidock, M., Milligan, G. (2006) Interactions between the Mas-related receptors MrgD and MrgE alter signalling and trafficking of MrgD. Mol Pharmacol. 69, 479-491.
83. Dickson, L., Barclay, Z., Mitchell, C., Fortheringham, H., Robertson, D., Holland, P., Rosie, R., Johnson, M., Lutz, E., Mitchell, R. (2008) Interaction between 5-HT2AR and the orphan GPCR TAAR6. In Keystone Symposium: G Protein - Coupled Receptors: New Insights in the Functiona Regulation and Clinical Application, ed. H.E. Hamm, P.J. Conn, J.P. Pin, O. Civelli, pp. 60. Killarney, Ireland: INEC-Ireland' s National Events & Conference Centre.
84. Neuhaus, E.M., Gisselmann, G., Zhang, W., Dooley, R., Stortkuhl, K., Hatt, H. (2005) Odorant receptor heterodimerization in the olfactory system of Drosophila melanogaster. Nat Neurosci. 8, 15-17.
85. Benton, R., Sachse, S., Michnick, S.W., Vosshall, L.B. (2006) Atypical membrane topology and heteromeric function of Drosophila odorant receptors in vivo. PLoS Biol. 4, e20.
86. Wicher, D., Schafer, R., Bauernfeind, R., Stensmyr, M.C., Heller, R., Heinemann, S.H., Hansson, B.S. (2008) Drosophila odorant receptors are both ligand-gated and cyclic-nucleotide-activated cation channels. Nature. 452, 1007-1011.
87. Sato, K., Pellegrino, M., Nakagawa, T., Nakagawa, T., Vosshall, L.B., Touhara, K. (2008) Insect olfactory receptors are heteromeric ligand-gated ion channels. Nature. 452, 1002-1006.
88. McLatchie, L.M., Fraser, N.J., Main, M.J., Wise, A., Brown, J., Thompson, N., Solari, R., Lee, M.G., Foord, S.M. (1998) RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature. 393, 333-339.
89. Little, K.D., Hemler, M.E., Stipp, C.S. (2004) Dynamic regulation of a GPCR - tetraspanin-G protein complex on intact cells: Central role of CD81 in facilitating GPR56-Galpha q/11 association. Mol Biol Cell. 15, 2375-2387.
90. Xu, L., Begum, S., Hearn, J.D., Hynes, R.O. (2006) GPR56, an atypical G protein - coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. Proc Natl Acad Sci U S A. 103, 9023-9028.
91. Marazziti, D., Mandillo, S., Di Pietro, C., Golini, E., Matteoni, R., Tocchini-Valentini, G.P. (2007) GPR37 associates with the dopamine transporter to modulate dopamine uptake and behavioral responses to dopaminergic drugs. Proc Natl Acad Sci U S A. 104, 9846-9851.
92. Riobo, N.A., Lu, K., Emerson Jr., C.P. (2006) Hedgehog signal transduction: Signal integration and cross talk in development and cancer. Cell Cycle. 5, 1612-1615.
93. Schwartz, T.W., Holst, B. (2007) Allosteric enhancers, allosteric agonists and ago - allosteric modulators: Where do they bind and how do they act? Trends Pharmacol Sci. 28, 366-373.
94. Neubig, R.R., Spedding, M., Kenakin, T., Christopoulos, A. (2003) International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on terms and symbols in quantitative pharmacology . Pharmacol Rev. 55, 597-606.
95. Binet, V., Brajon, C., Le Corre, L., Acher, F., Pin, J.P., Prezeau, L. (2004) The heptahelical domain of GABA(B2) is activated directly by CGP7930, a positive allosteric modulator of the GABA(B) receptor. J Biol Chem. 279, 29085-29091.
96. Maenhaut, C., Van Sande, J., Libert, F., Abramowicz, M., Parmentier, M., Vanderhaegen, J.J., Dumont, J.E., Vassart, G., Schiffmann, S. (1990) RDC8 codes for an adenosine A2 receptor with physiological constitutive activity. Biochem Biophys Res Commun. 173, 1169-1178.
97. Stoddart, L.A., Brown, A.J., Milligan, G. (2007) Uncovering the pharmacology of the G protein-coupled receptor GPR40: High apparent constitutive activity in guanosine 5 '-O-(3-[35S]thio)triphosphate binding studies reflects binding of an endogenous agonist. Mol Pharmacol. 71, 994-1005.
98. Seuwen, K., Ludwig, M.G., Wolf, R.M. (2006) Receptors for protons or lipid messengers or both? J Recept Signal Transduct Res. 26, 599-610.
99. Zhang, J.V., Ren, P.G., Avsian-Kretchmer, O., Luo, C.W., Rauch, R., Klein, C., Hsueh, A.J. (2005) Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin' s effects on food intake. Science. 310, 996-999.
100. Chartrel, N., Alvear-Perez, R., Leprince, J., Iturrioz, X., Reaux-Le Goazigo, A., Audinot, V., Chomarat, P., Coge, F., Nosjean, O., Rodriguez, M., Galizzi, J.P., Boutin, J.A., Vaudry, H., Llorens-Cortes, C. (2007) Comment on "Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin' s effects on food intake. " Science. 315, 766.
101. Holst, B., Egerod, K.L., Schild, E., Vickers, S.P., Cheetham, S., Gerlach, L.O., Storjohann, L., Stidsen, C.E., Jones, R., Beck-Sickinger, A.G., Schwartz, T.W. (2007) GPR39 signaling is stimulated by zinc ions but not by obestatin. Endocrinology. 148, 13-20.
102. Otto, C., Rohde-Schulz, B., Schwarz, G., Fuchs, I., Klewer, M., Brittain, D., Langer, G., Bader, B., Prelle, K., Nubbemeyer, R., Fritzemeier, K.H. (2008) GPR30 localizes to the endoplasmic reticulum and is not activated by estradiol. Endocrinology. 149, 4846-4856.
103. Prossnitz, E.R., Oprea, T.I., Sklar, L.A., Arterburn, J.B. (2008) The ins and outs of GPR30: A transmembrane estrogen receptor. J Steroid Biochem Mol Biol. 109, 350-353.
104. Levoye, A., Dam, J., Ayoub, M.A., Guillaume, J.L., Jockers, R. (2006) Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers. EMBO Rep. 7, 1094-1098.
105. Kniazeff, J., Galvez, T., Labesse, G., Pin, J.P. (2002) No ligand binding in the GB2 subunit of the GABA(B) receptor is required for activation and allosteric interaction between the subunits. J Neurosci. 22, 7352-7361.
106. Dufourny, L., Levasseur, A., Migaud, M., Callebaut, I., Pontarotti, P., Malpaux, B., Monget, P. (2008) GPR50 is the mammalian ortholog of Mel1c: Evidence of rapid evolution in mammals. BMC Evol Biol. 8, 105.
107. Kohno, M., Hasegawa, H., Inoue, A., Muraoka, M., Miyazaki, T., Oka, K., Yasukawa, M. (2006) Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem Biophys Res Commun. 347, 827-832.
108. Sugo, T., Tachimoto, H., Chikatsu, T., Murakami, Y., Kikukawa, Y., Sato, S., Kikuchi, K., Nagi, T., Harada, M., Ogi, K., Ebisawa, M., Mori, M. (2006) Identification of a lysophosphatidylserine receptor on mast cells. Biochem Biophys Res Commun. 341, 1078-1087.
109. Ryberg, E., Larsson, N., Sjogren, S., Hjorth, S., Hermansson, N.O., Leonova, J., Elebring, T., Nilsson, K., Drmota, T., Greasley, P.J. (2007) The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 152, 1092-1101.
110. Kotarsky, K., Boketoft, A., Bristulf, J., Nilsson, N.E., Norberg, A., Hansson, S., Owman, C., Sillard, R., Leeb-Lundberg, L.M., Olde, B. (2006) Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes. J Pharmacol Exp Ther. 318, 619-628.
111. Lee, C.W., Rivera, R., Gardell, S., Dubin, A.E., Chun, J. (2006) GPR92 as a new G12/13-and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5. J Biol Chem. 281, 23589-23597.
112. Soga, T., Ohishi, T., Matsui, T., Saito, T., Matsumoto, M., Takasaki, J., Matsumoto, S., Kamohara, M., Hiyama, H., Yoshida, S., Momose, K., Ueda, Y., Matsushime, H., Kobori, M., Furuichi, K. (2005) Lysophosphatidylcholine enhances glucose-dependent insulin secretion via an orphan G-protein-coupled receptor. Biochem Biophys Res Commun. 326, 744-751.
113. Balabanian, K., Lagane, B., Infantino, S., Chow, K.Y., Harriague, J., Moepps, B., Arenzana-Seisdedos, F., Thelen, M., Bachelerie, F. (2005) The chemokine SDF-1/ CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes . J Biol Chem. 280, 35760-35766.
114. Pasternack, S.M., von Kugelgen, I., Aboud, K.A., Lee, Y.A., Ruschendorf, F., Voss, K., Hillmer, A.M., Molderings, G.J., Franz, T., Ramirez, A., Nurnberg, P., Nothen, M.M., Betz, R.C. (2008) G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat Genet. 40, 329-334.
115. Hase, M., Yokomizo, T., Shimizu, T., Nakamura, M. (2008) Characterization of an orphan G protein-coupled receptor, GPR20, that constitutively activates Gi proteins . J Biol Chem. 283, 12747-12755.
116. Adams, J.W., Wang, J., Davis, J.R., Liaw, C., Gaidarov, I., Gatlin, J., Dalton, N.D., Gu, Y., Ross Jr., J.R., Behan, D., Chien, K.R., Connolly, D. (2008) Myocardial expression, signaling, and function of GPR22: A protective role for an orphan G - protein coupled receptor. Am J Physiol Heart Circ Physiol. 295, H509-H521.
117. Jones, P.G., Nawoschik, S.P., Sreekumar, K., Uveges, A.J., Tseng, E., Zhang, L., Johnson, J., He, L., Paulsen, J.E., Bates, B., Pausch, M.H. (2007) Tissue distribution and functional analyses of the constitutively active orphan G protein coupled receptors, GPR26 and GPR78. Biochim Biophys Acta. 1770, 890-901.
118. Ge, H., Weiszmann, J., Reagan, J.D., Gupte, J., Baribault, H., Gyuris, T., Chen, J.L., Tian, H., Li, Y. (2008) Elucidation of signaling and functional activities of an orphan GPCR, GPR81. J Lipid Res. 49, 797-803.
119. Hirano, M., Zang, L., Oka, T., Ito, Y., Shimada, Y., Nishimura, Y., Tanaka, T. (2006) Novel reciprocal regulation of cAMP signaling and apoptosis by orphan G-protein-coupled receptor GPRC5A gene expression. Biochem Biophys Res Commun. 351, 185-191.
120. Rosenkilde, M.M., Benned-Jensen, T., Andersen, H., Holst, P.J., Kledal, T.N., Luttichau, H.R., Larsen, J.K., Christensen, J.P., Schwartz, T.W. (2006) Molecular pharmacological phenotyping of EBI2. An orphan seven-transmembrane receptor with constitutive activity. J Biol Chem. 281, 13199-13208.
121. Hoshii, T., Takeo, T., Nakagata, N., Takeya, M., Araki, K., Yamamura, K. (2007) LGR4 regulates the postnatal development and integrity of male reproductive tracts in mice. Biol Reprod. 76, 303-313.