Receptor Identification: Advances in Ligands and Transmitters Discovery

  • Sandeep Arora Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab-140401
  • Govindrajan Raghavan Dabur International, Dubai
  • Avaneesh Kumar Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab-140401
Keywords: Orphan G-protein-coupled receptors, Hybridisation, PCR, cysteinyl leukotriene CysLT1 and Cys T2, hepatointestinal leukotriene B4, motilin, Ghrelin, Growth hormone-releasing peptide

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.

Downloads

Download data is not yet available.

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
2014-05-07
How to Cite
Sandeep Arora, Govindrajan Raghavan, & Avaneesh Kumar. (2014). Receptor Identification: Advances in Ligands and Transmitters Discovery. Journal of Pharmaceutical Technology, Research and Management, 2(1), 61-75. https://doi.org/10.15415/jptrm.2014.21005
Section
Articles

Most read articles by the same author(s)

1 2 > >>