Receptor Identification: Advances in Ligands and Transmitters Discovery
Abstract
Receptor identification is an integral part of drug discovery and development. By the beginning of the next millennium, the search for the natural ligands of the orphan G-protein-coupled receptors will lead to the discovery of so many new peptides that it may well double their present number. It has recently become evident that all types of chemical messengers, hormones and transmitters act through membrane receptors which constitute our largest superfamily of proteins, i.e. the G protein-coupled receptors. The development of targeted therapies has revolutionized the treatment of various chronic diseases. Receptors have well-conserved regions that are recognized and activated by hormones and neurotransmitters. These ligands are peptides, lipids or biogenic amines, and act as transmitter molecules. Identification of orphan receptors include screening, binding and reverse engineering that help to find out cysteinyl leukotriene CysLT1 and Cys T2, hepatointestinal leukotriene B4, motilin, Ghrelin, Growth hormone-releasing peptide and growth hormone secretagogue receptor and many more. Techniques involved in screening of receptors include low stringency hybridization followed by PCR-derived approaches helps to discover various orphan g protein couple recptors (oGPCR). The discovery of the oGPCR represents a hallmark in neuroscience research, and the exploitation of its numerous physiological and pathophysiological functions is a promising avenue for therapeutic applications.
- Page Number : 61-75
- Keywords
Orphan G-protein-coupled receptors, Hybridisation, PCR, cysteinyl leukotriene CysLT1 and Cys T2, hepatointestinal leukotriene B4, motilin, Ghrelin, Growth hormone-releasing peptide - DOI Number
10.15415/jptrm.2014.21005 -
Authors
- Sandeep AroraChitkara College of Pharmacy, Chitkara University, Rajpura, Punjab-140401
- Govindrajan RaghavanDabur International, Dubai
- Avaneesh KumarChitkara College of Pharmacy, Chitkara University, Rajpura, Punjab-140401
References
- A.D. et al. (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273, 974–977. https://doi.org/10.1126/science.273.5277.974
- Aiyar, N. et al. (1996) A cDNA encoding the calcitonin gene-related peptide type 1 receptor. J. Biol. Chem. 271, 11325–11329.
- Ames, R.S. et al. (1999) Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature 401, 282–286. https://doi.org/10.1038/45809
- An, S. et al. (2000) Sphingosine -1-phosphate-induced cell proliferation, survival, and related signaling events mediated by G protein-coupled receptors edg3 and edg5. J. Biol. Chem. 275, 288–296. https://doi.org/10.1074/jbc.275.1.288
- Bachner, D. et al. (1999) Identification of melanin concentrating hormone (MCH) as the natural ligand for the orphan somatostatin-like receptor 1 (SLC-1). FEBS Lett. 457, 522–524. https://doi.org/10.1016/S0014-5793(99)01092-3
- Birgul, N. et al. (1999) Reverse physiology in Drosophila: identification of a novel allatostatinlikeneuropeptide and its cognate receptor structurally related to the mammalian somatostatin/galanin/opioid receptor family. EMBO J. 18, 5892–5900. https://doi.org/10.1093/emboj/18.21.5892
- Bonini, J.A. et al. (2000) Identification and characterization of two G protein-coupled receptors for neuropeptide FF. J. Biol. Chem. 275,39324–39331. https://doi.org/10.1074/jbc.M004385200
- Bowers, C.Y. (1998) Growth hormone-releasing peptide (GHRP). Cell. Mol. Life Sci. 54, 1316–1329. https://doi.org/10.1007/s000180050257
- Brighton PJ, Szekeres PG, Willars GB. (2004) “Neuromedin U and its receptors: structure, function, and physiological roles.” Pharmacol Rev ; 56 (2):231-48.
- Bruce Blumberg and Ronald M. Evans (1998) “Orphan nuclear receptors—new ligands and new possibilities” Genes & Dev. 12: 3149-3155. https://doi.org/10.1101/gad.12.20.3149
- Bunzow, J. R., Van Tol, H. H., Grandy, D. K., Albert, P., Salon, J., Christie, M., et al. (1988). Cloning and expression of a rat D2 dopamine receptor cDNA. Nature 336, 783–787. https://doi.org/10.1038/336783a0
- Cao, J. et al. (1998) Cloning and characterization of a cDNA encoding a novel subtype of rat thyrotropinreleasing hormone receptor. J. Biol. Chem. 273, 32281-32287. https://doi.org/10.1074/jbc.273.48.32281
- Cha, H.J., Park, M.T., Chung, H.Y., Kim, N.D., Sato, H., Seiki, M., and Kim, K.W. (1998). Ursolic acid-induced down-regulation of MMP-9 gene is mediated through the nuclear translocation of glucocorticoid receptor in HT1080 human fibrosarcoma cells. Oncogene 16, 771–778. https://doi.org/10.1038/sj.onc.1201587
- Chambers, J. et al. (1999) Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1. Nature 400, 261–265. https://doi.org/10.1038/22313
- Chambers, J.K. et al. (2000) A G protein-coupled receptor for UDP-glucose. J. Biol. Chem. 275, 10767–10771. https://doi.org/10.1074/jbc.275.15.10767
- Chandrasekaran B, Dar O, McDonagh T. (2008) “The role of apelin in cardiovascular function and heart failure” Eur J Heart Fail 10 (8):725-732. https://doi.org/10.1016/j.ejheart.2008.06.002
- Civelli, O. (1998). Functional genomics: the search for novel neurotransmitters and neuropeptides. FEBS Lett 430, 55–58. https://doi.org/10.1016/S0014-5793(98)00524-9
- Civelli, O. (2005). GPCR deorphanizations: the novel, the known and the unexpected transmitters. Trends Pharmacol Sci 26, 15–19. https://doi.org/10.1016/j.tips.2004.11.005
- Civelli, O. (2014 in press). Orphan GPCRs in the regulation of sleep and circadian rhythm. FEBS J. 272, 5673-5674. https://doi.org/10.1111/j.1742-4658.2005.04867.x
- Civelli, O., Nothacker, H. P., Saito, Y., Wang, Z., Lin, S. H., & Reinscheid, R.K. (2001). Novel neurotransmitters as natural ligands of orphan G-proteincoupled receptors.
- Trends Neurosci 24, 230–237. https://doi.org/10.1016/S0166-2236(00)01763-X
- D.I. et al. (2000) Cutting edge: Identification of the orphan receptor G-protein-coupled receptor 2 as CCR10, a specific receptor for the chemokine eskine. J. Immunol. 164, 3460–3464. https://doi.org/10.4049/jimmunol.164.7.3460
- David J. Mangelsdorf’ and Ronald M. Evans (1995), Cell, Vol. 83, 841-850, Cell Press. https://doi.org/10.1016/0092-8674(95)90200-7
- De Lecea L, Sutcliffe JG (2005). “The hypocretins and sleep.” FEBS J; 272 (22):5675-88. https://doi.org/10.1111/j.1742-4658.2005.04981.x
- De Lecea, L. et al. (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. U. S. A. 95, 322–327.
- Douglass, J., Civelli, O., & Herbert, E. (1984). Polyprotein gene expression: generation of diversity of neuroendocrine peptides. Ann Rev Biochem 53, 665–715. https://doi.org/10.1146/annurev.bi.53.070184.003313
- Elshourbagy, N.A. et al. (2000) Receptor for the pain modulatory neuropeptides NPFF and NPAF is an orphan G-protein-coupled receptor. J. Biol. Chem.275, 25965–25971. https://doi.org/10.1074/jbc.M004515200
- Fargin, A., Raymond, J. R., Lohse, M. J., Kobilka, B. K., Caron, M. J., & Lefkowitz, R. J. (1988). The genomic clone G-21 which resembles a betaadrenergic receptor sequence encodes the 5-HT1A receptor. Nature 335, 358–360. https://doi.org/10.1038/335358a0
- Feighner, S.D. et al. (1999) Receptor for motilin identified in the human gastrointestinal system. Science 284, 2184–2188. DOI: 10.1126/science.284.5423.2184
- Fukushima, N. et al. (1998) A single receptor encoded by vzg-1/lpa1/edg-2 couples to G proteins and mediates multiple cellular responses to lysophosphatidic acid. Proc. Natl. Acad. Sci. U. S. A 95, 6151–6156. https://doi.org/10.1073/pnas.95.11.6151
- Goldstein, A. (1974). Principles of Drug Action: The Basis of Pharmacology.(2nd ed.). West Sussex & New York’ Wiley.
- Hedrick, J.A. et al. (2000) Identification of a human gastrointestinal tract and immune system receptor for the peptide neuromedin U. Mol. Pharmacol. 58, 870–875. https://doi.org/10.1124/mol.58.4.870
- Heise, C.E. et al. (2000) Characterization of the human cysteinyl leukotriene 2 (CysLT2)receptor. J. Biol. Chem. 275, 30531–30536. https://doi.org/10.1074/jbc.M003490200
- Hinuma, S., Habata, Y., Fujii, R., Kawamata, Y., Hosoya, M., Fukusumi, S., et al. (1998). A prolactin releasing peptide in the brain. Nature 393, 272–276. https://doi.org/10.1038/30515
- Hinuma, S., Onda, H., & Fujino, M. (1999). The quest for novel bioactive peptides utilizing orphan seven-transmembrane-domain receptors. J Mol Med 77, 495– 504. https://doi.org/10.1007/s001090050403
- Hotamisligil, G.S., Shargill, N.S., and Spiegelman, B.M. (1993). Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 87–91. https://doi.org/10.1126/science.7678183
- Huh, J.R., Leung, M.W.L., Huang, P.X., Ryan, D.A., Krout, M.R., Malapaka, R.R.V., Chow, J., Manel, N., Ciofani, M., Kim, S.V., et al. (2011). Digoxin and its derivatives suppress
- TH17 cell differentiation by antagonizing RORgt activity. Nature 472, 486–490. https://doi.org/10.1038/nature09978
- Im, D.S. et al. (2000) Characterization of a novel sphingosine 1-phosphate receptor, edg-8. J. Biol. Chem.275, 14281–14286. https://doi.org/10.1074/jbc.275.19.14281
- Im, D.S. et al. (2000) Molecular cloning and characterization of a lysophosphatidic acid receptor, edg-7, expressed in prostate. Mol. Pharmacol. 57,753–759. https://doi.org/10.1124/mol.57.4.753
- Itadani, H. et al. (1998) Cloning and characterization of a new subtype of thyrotropin-releasing hormone receptors. Biochem. Biophys. Res. Commun. 250, 68–71.
- Jeffrey S. Mogil and Gavril W. Pasternak (2001) “The Molecular and Behavioral Pharmacology of the Orphanin FQ/Nociceptin Peptide and Receptor Family. Pharmacological Reviews 53(3) 381-415.
- Kallen, J.A., Schlaeppi, J.M., Bitsch, F., Geisse, S., Geiser, M., Delhon, I., and Fournier, B. (2002). X-ray structure of the hRORα LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORα. Structure 10, 1697–1707. https://doi.org/10.1016/S0969-2126(02)00912-7
- Kamohara, M. et al. (2000) Molecular cloning and characterization of another leukotriene B4 receptor. J. Biol. Chem. 275, 27000–27004. https://doi.org/10.1074/jbc.C000382200
- Kojima, M. et al. (1999) Ghrelin is a growth hormone-releasing acylated peptide from stomach. Nature 402, 656–660. https://doi.org/10.1038/45230
- Lagathu, C., Yvan-Charvet, L., Bastard, J.P., Maachi, M., Quignard-Boulangé, A., Capeau, J., and Caron, M. (2006). Long-term treatment with interleukin- 1beta induces insulin resistance in murine and human adipocytes. Diabetologia 49, 2162–2173. https://doi.org/10.1007/s00125-006-0335-z
- Lee, J.M., Lee, Y.K., Mamrosh, J.L., Busby, S.A., Griffin, P.R., Pathak, M.C.,Ortlund, E.A., and Moore, D.D. (2011). A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature 474, 506–510. https://doi.org/10.1038/nature10111
- Lee, M.J. et al. (1998) Sphingosine-1-phosphate as a ligand for the G protein-coupled receptoredg-1. Science 279, 1552–1555. https://doi.org/10.1126/science.279.5356.1552
- Lee, Y.K., and Moore, D.D. (2008). Liver receptor homolog-1, an emerging metabolic modulator. Front. Biosci. 13, 5950–5958. https://doi.org/10.2741/3128
- Lembo, P.M. et al. (1999) The receptor for the orexigenic peptide melanin-concentrating hormone is a G-protein-coupled receptor. Nat. Cell Biol. 1, 267–271. https://doi.org/10.1038/12978
- Lenz, C. et al. (2000) Molecular cloning and genomic organization of a second probable allatostatin receptor from Drosophila melanogaster. Biochem. Biophys. Res. Commun. 273, 571–577.
- Libert, F., Parmentier, M., Lefort, A., Dinsart, C., Van Sand, J., Maenhaut, C., et al. (1989). Selective amplification and cloning of four new members of the G protein-coupled receptor family. Science 244, 569– 572. https://doi.org/10.1126/science.2541503
- Libert, F., Schiffmann, S. N., Lefort, A., Parmentier, M., Gerard, C., Dumont, J. E., et al. (1991b). The orphan receptor cDNA RDC7 encodes an A1 adenosine receptor. EMBO J 10, 1677– 1682.
- Libert, F., Vassart, G., & Parmentier, M. (1991a). Current development in G protein-coupled receptors. Curr Opin Cell Biol 3, 218–223. https://doi.org/10.1016/0955-0674(91)90142-L
- Liu, Q. et al. (1999) Identification of urotensin II as the endogenous ligand for the orphan G-protein coupled receptor GPR14. Biochem. Biophys. Res. Commun.266, 174–178. https://doi.org/10.1006/bbrc.1999.1796
- Lovenberg, T.W. et al. (1999) Cloning and functional expression of the human histamine H3 receptor. Mol. Pharmacol. 55, 1101–1107.
- Lynch, K.R. et al. (1999) Characterization of the human cysteinyl leukotriene CysLT1 receptor. Nature 399, 789–793. https://doi.org/10.1038/21658
- McLatchie, L.M. et al. (1998) RAMPS regulate the transport and ligand specificity of the calcitonin receptor-like receptor. Nature 393, 333–339. https://doi.org/10.1038/30666
- Meunier, J.C. et al. (1995) Isolation and structure of the endogenous agonist of opioid receptor-like ORL1 receptor. Nature 377, 532–535. https://doi.org/10.1038/377532a0
- Morell M, Souza-Moreira L, Caro M, O’Valle F, Forte-Lago I, de Lecea L, Gonzalez-Rey, E Delgado M. Analgesic effect of the neuropeptide cortistatin in murine models of arthritic inflammatory pain. Arthritis Rheum. 2013 May; 65(5):1390-401. https://doi.org/10.1002/art.37877
- Mori, M. et al. (1999) Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14). Biochem. Biophys. Res. Commun. 265, 123–129. https://doi.org/10.1006/bbrc.1999.1640
- Nothacker, H.P. et al. (1999) Identification of the natural ligand of an orphan G protein-coupled receptor involved in the regulation of vasoconstriction. Nat. Cell Biol. 1, 383–385. https://doi.org/10.1038/14081
- Okamoto, H. et al. (1999) Edg3 is a functional receptor specific for sphingosine 1-phosphate and sphingosyl phosphorylcholine with signalling characteristics distinct from edg1 and agr16. Biochem. Biophys. Res. Commun. 260, 203–208. https://doi.org/10.1006/bbrc.1999.0886
- Patchett, A.A. et al. (1995), Design and biological activities of L-163,191 (MK-0677): a potent, orally active growth hormone secretagogue. Proc. Natl.Acad. Sci. U. S. A. 92, 7001–7005. https://doi.org/10.1073/pnas.92.15.7001
- Pyne, S. and Pyne, N.J. (2000) Sphingosine 1- phosphate signaling in mammalian cells. Biochem. J. 349, 385–402. https://doi.org/10.1042/0264-6021:3490385
- R.S. et al. (1996) Molecular cloning and characterization of the human anaphylatoxin C3a receptor. J. Biol. Chem. 271, 20231–20234. https://doi.org/10.1074/jbc.271.34.20231
- Reinscheid, R.K. et al. (1995) Orphanin FQ: a neuropeptide that activates an opioid-like G protein coupled receptor. Science 270, 792–794. https://doi.org/10.1126/science.270.5237.792
- Saito, Y. et al. (1999) Molecular characterization of the melanin-concentrating-hormone receptor. Nature 400, 265–269. https://doi.org/10.1038/22321
- Sakurai, T. et al. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585. https://doi.org/10.1016/S0092-8674(00)80949-6
- Sarau, H.M. et al. (1999) Identification, molecular cloning, expression, and characterization of a cysteinyl leukotriene receptor. Mol. Pharmacol. 56, 657–663.
- Sato T, Suzuki T, Watanabe H, Kadowaki A, Fukamizu A, Liu PP, Kimura A, Ito H, Penninger JM, Imai Y, Kuba K. (2013) “Apelin is a positive regulator of ACE2 in failing hearts” J Clin Invest; 123(12):5203–5211. https://doi.org/10.1172/JCI69608
- Shimomura, Y. et al. (1999) Isolation and identification of melanin-concentrating hormone as the endogenous ligand of the SLC-1 receptor. Biochem. Biophys. Res. Commun. 261, 622–626. https://doi.org/10.1006/bbrc.1999.1104
- Smith RG, Leonard R, Bailey AR, Palyha O, Feighner S, Tan C, Mckee KK, Pong SS, Griffin P, Howard A. (2001) “Growth hormone secretagogue receptor family members and ligands. Endocrine 14 (1): 9-14. https://doi.org/10.1385/ENDO:14:1:009
- Steppan, C.M., Bailey, S.T., Bhat, S., Brown, E.J., Banerjee, R.R., Wright, C.M., Patel, H.R., Ahima, R.S., and Lazar, M.A. (2001). The hormone resisting links obesity to diabetes. Nature 409, 307–312. https://doi.org/10.1038/35053000
- Tatemoto, K. et al. (1998) Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem.Biophys. Res. Commun. 251, 471–476.
- https://doi.org/10.1006/bbrc.1998.9489
- Thomas P. Burris, Scott A. Busby, 2 and Patrick R. Griffin1 Chemistry & Biology Review Targeting Orphan Nuclear Receptors for Treatment of Metabolic Diseases and
- Autoimmunity Chemistry & Biology 19, 2012 (51-59). https://doi.org/10.1016/j.chembiol.2011.12.011
- Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang XP, Trapella C, Guerrini R, Calo G, Roth BL, Cherezov V, Stevens RC. “Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic.” Nature 2012 May 16; 485 (7398):395-9. https://doi.org/10.1038/nature11085
- Vassilatis, D. K., Hohmann, J. G., Zeng, H., Li, F., Ranchalis, J. E., Mortrud, M. T., et al. (2003). The G protein-coupled receptor repertoires of human and mouse. Proc Natl Acad Sci U S A 100, 4903– 4908. https://doi.org/10.1073/pnas.0230374100
- Wang, S. et al. (2000) A novel hepatointestinal leukotriene B4 receptor: cloning and functional characterization. J. Biol. Chem. 275, 40686-40694.https://doi.org/10.1074/jbc.M004512200
- Wang, Y., Kumar, N., Solt, L.A., Richardson, T.I., Helvering, L.M., Crumbley, C., Garcia- Ordonez, R.A., Stayrook, K.R., Zhang, X., Novick, S., et al. (2010b). Modulation of retinoic acid receptorrelated orphan receptor alpha and gamma activity by 7-oxygenated sterol ligands. J. Biol. Chem. 285, 5013–5025. https://doi.org/10.1074/jbc.M109.080614
- Wurtman RJ (2006). “Narcolepsy and the hypocretins.” Metabolism 55 (10): S 36-9. https://doi.org/10.1016/j.metabol.2006.07.011
- Xu, T., Wang, X., Zhong, B., Nurieva, R.I., Ding, S., and Dong, C. (2011). Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of ROR gamma t protein. J. Biol. Chem. 286, 22707–22710. https://doi.org/10.1074/jbc.C111.250407
- Xu, Y. et al. (2000) Sphingosylphosphorylcholine is a ligand for ovarian cancer G-protein-coupled receptor 1. Nat. Cell Biol. 2, 261–267. https://doi.org/10.1038/35010529
- Yamauchi, T., Nio, Y., Maki, T., Kobayashi, M., Takazawa, T., Iwabu, M., Okada-Iwabu, M., Kawamoto, S., Kubota, N., Kubota, T., et al. (2006). Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat. Med. 13, 332–339. https://doi.org/10.1038/nm1557
- Yokomizo, T. et al. (1997) A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 387, 620–624. https://doi.org/10.1038/42506
Published Date : 2014-05-20