The G Protein-Coupled Receptors Deorphanization Landscape

[en] G protein-coupled receptors (GPCRs) are usually highlighted as being both the largest family of membrane proteins and the most productive source of drug targets. However, most of the GPCRs are understudied and hence cannot be used immediately for innovative therapeutic strategies. Besides, there are still around 100 orphan receptors, with no described endogenous ligand and no clearly defined function. The race to discover new ligands for these elusive receptors seems to be less intense than before. Here, we present an update of the various strategies employed to assign a function to these receptors and to discover new ligands. We focus on the recent advances in the identification of endogenous ligands with a detailed description of newly deorphanized receptors. Replication being a key parameter in these endeavors, we also discuss the latest controversies about problematic ligand-receptor pairings. In this context, we propose several recommendations in order to strengthen the reporting of new ligand-receptor pairs.

Disciplines :

Biochemistry, biophysics & molecular biology
Pharmacy, pharmacology & toxicology

Author, co-author :

Laschet, Céline ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique

Dupuis, Nadine

Hanson, Julien ; Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique

Language :

English

Title :

The G Protein-Coupled Receptors Deorphanization Landscape

Publication date :

July 2018

Journal title :

Biochemical Pharmacology

ISSN :

0006-2952

eISSN :

1873-2968

Publisher :

Elsevier, Netherlands

Volume :

153

Pages :

62-74

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 14 February 2018

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131 (15 by ULiège)

Number of downloads

2 (2 by ULiège)

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Bibliography

Hauser, A.S., Attwood, M.M., Rask-Andersen, M., Schiöth, H.B., Gloriam, D.E., Trends in GPCR drug discovery: new agents, targets and indications. Nat. Rev. Drug Discov., 2, 2017, 1, 10.1038/nrd.2017.178.
Rask-Andersen, M., Almén, M.S., Schiöth, H.B., Trends in the exploitation of novel drug targets. Nat. Rev. Drug Discov. 10 (2011), 579–590, 10.1038/nrd3478.
Overington, J.P., Al-Lazikani, B., Hopkins, A.L., How many drug targets are there?. Nat. Rev. Drug Discov. 5 (2006), 993–996, 10.1038/nrd2199.
Sriram, K., Insel, P.A., GPCRs as targets for approved drugs: How many targets and how many drugs?. Mol. Pharmacol., 2018, 10.1124/mol.117.111062.
Nygaard, R., Zou, Y., Dror, R.O., Mildorf, T.J., Arlow, D.H., Manglik, A., et al. The dynamic process of β2-adrenergic receptor activation. Cell 152 (2013), 532–542, 10.1016/j.cell.2013.01.008.
Kenakin, Biased signalling and allosteric machines: new vistas and challenges for drug discovery. Br. J. Pharmacol. 165 (2012), 1659–1669, 10.1111/j.1476-5381.2011.01749.x.
Ferguson, S.S., Evolving concepts in G protein-coupled receptor endocytosis: the role in receptor desensitization and signaling. Pharmacol. Rev. 53 (2001), 1–24.
Shenoy, S.K., McDonald, P.H., Kohout, T.A., Lefkowitz, R.J., Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science 294 (2001), 1307–1313, 10.1126/science.1063866.
DeWire, S.M., Ahn, S., Lefkowitz, R.J., Lefkowitz, R.J., Shenoy, S.K., Beta-arrestins and cell signaling. Annu. Rev. Physiol. 69 (2007), 483–510, 10.1146/annurev.ph.69.013107.100021.
Noma, T., Lemaire, A., Naga Prasad, S.V., Barki-Harrington, L., Tilley, D.G., Chen, J., et al. Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J. Clin. Invest. 117 (2007), 2445–2458, 10.1172/JCI31901.
Grundmann, M., Merten, N., Malfacini, D., Inoue, A., Preis, P., Simon, K., et al. Lack of beta-arrestin signaling in the absence of active G proteins. Nat. Commun., 9, 2018, 341, 10.1038/s41467-017-02661-3.
O'Hayre, M., Eichel, K., Avino, S., Zhao, X., Steffen, D.J., Feng, X., et al. Genetic evidence that β-arrestins are dispensable for the initiation of β2-adrenergic receptor signaling to ERK. Sci. Signaling, 10, 2017, 10.1126/scisignal.aal3395.
Irannejad, R., Tomshine, J.C., Tomshine, J.R., Chevalier, M., Mahoney, J.P., Steyaert, J., et al. Conformational biosensors reveal GPCR signalling from endosomes. Nature 495 (2013), 534–538, 10.1038/nature12000.
Thomsen, A.R.B., Plouffe, B., Cahill, T.J., Shukla, A.K., Tarrasch, J.T., Dosey, A.M., et al. GPCR-G protein-β-arrestin super-complex mediates sustained G protein signaling. Cell, 2016, 907–919, 10.1016/j.cell.2016.07.004.
Rang, H.P., The receptor concept: pharmacology's big idea. Br. J. Pharmacol. 147 (2006), S9–S16, 10.1038/sj.bjp.0706457.
Libert, F., Parmentier, M., Lefort, A., Dinsart, C., Van Sande, J., Maenhaut, C., et al. Selective amplification and cloning of four new members of the G protein-coupled receptor family. Science 244 (1989), 569–572.
Mills, A., Duggan, M.J., Orphan seven transmembrane domain receptors: reversing pharmacology. Trends Biotechnol. 12 (1994), 47–49, 10.1016/0167-7799(94)90099-X.
Lander, E.S., Linton, L.M., Birren, B., Nusbaum, C., Zody, M.C., Baldwin, J., et al. Initial sequencing and analysis of the human genome. Nature 409 (2001), 860–921, 10.1038/35057062.
Fredriksson, R., Lagerström, M.C., Lundin, L.-G., Schiöth, H.B., The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol. Pharmacol. 63 (2003), 1256–1272, 10.1124/mol.63.6.1256.
Foord, S.M., Bonner, T.I., Neubig, R.R., Rosser, E.M., Pin, J.-P., Davenport, A.P., et al. International union of pharmacology. XLVI. G protein-coupled receptor list. Pharmacol. Rev. 57 (2005), 279–288, 10.1124/pr.57.2.5.
Alexander, S.P., Kelly, E., Marrion, N.V., Peters, J.A., Faccenda, E., Harding, S.D., et al. The concise guide to pharmacology 2017/18: overview. Br. J. Pharmacol. 174 (2017), S1–S16, 10.1111/bph.13882.
Davenport, A.P., Alexander, S.P.H., Sharman, J.L., Pawson, A.J., Benson, H.E., Monaghan, A.E., et al. International union of basic and clinical pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol. Rev. 65 (2013), 967–986, 10.1124/pr.112.007179.
Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R.M., Tanaka, H., et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92 (1998), 573–585.
Mieda, M., The roles of orexins in sleep/wake regulation. Neurosci. Res. 118 (2017), 56–65, 10.1016/j.neures.2017.03.015.
Keener, A., Drugs that made headlines in 2014. Nat. Med. 20 (2014), 1370–1371, 10.1038/nm1214-1370.
Edwards, A.M., Isserlin, R., Bader, G.D., Frye, S.V., Willson, T.M., Yu, F.H., Too many roads not taken. Nat. News 470 (2011), 163–165, 10.1038/470163a.
Roth, B.L., Kroeze, W.K., Integrated approaches for genome-wide interrogation of the druggable non-olfactory G protein coupled receptor superfamily. J. Biol. Chem., 2015, 10.1074/jbc.R115.654764.
Levoye, A., Jockers, R., Alternative drug discovery approaches for orphan GPCRs. Drug. Discov. Today 13 (2008), 52–58, 10.1016/j.drudis.2007.09.011.
Levoye, A., Dam, J., Ayoub, M.A., Guillaume, J.-L., Jockers, R., Do orphan G-protein-coupled receptors have ligand-independent functions? New insights from receptor heterodimers. EMBO Rep. 7 (2006), 1094–1098, 10.1038/sj.embor.7400838.
Levoye, A., Dam, J., Ayoub, M.A., Guillaume, J.-L., Couturier, C., Delagrange, P., et al. The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization. EMBO J. 25 (2006), 3012–3023, 10.1038/sj.emboj.7601193.
Milasta, S., Pediani, J., Appelbe, S., Trim, S., Wyatt, M., Cox, P., et al. Interactions between the Mas-related receptors MrgD and MrgE alter signalling and trafficking of MrgD. Mol. Pharmacol. 69 (2006), 479–491, 10.1124/mol.105.018788.
Kroeze, W.K., Sassano, M.F., Huang, X.-P., Lansu, K., McCorvy, J.D., Giguère, P.M., et al. PRESTO-Tango as an open-source resource for interrogation of the druggable human GPCRome. Nat. Struct. Mol. Biol., 2015, 10.1038/nsmb.3014.
Ritter, S.L., Hall, R.A., Fine-tuning of GPCR activity by receptor-interacting proteins. Nat. Rev. Mol. Cell Biol. 10 (2009), 819–830, 10.1038/nrm2803.
Hay, D.L., Garelja, M.L., Poyner, D.R., Walker, C.S., Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR review 25. Br. J. Pharmacol. 175 (2018), 3–17, 10.1111/bph.14075.
Nijenhuis, W.A., Oosterom, J., Adan, R.A., AgRP(83–132) acts as an inverse agonist on the human-melanocortin-4 receptor. Mol. Endocrinol. 15 (2001), 164–171, 10.1210/mend.15.1.0578.
Rajagopal, S., Kim, J., Ahn, S., Craig, S., Lam, C.M., Gerard, N.P., et al. arrestin- but not G protein-mediated signaling by the “decoy” receptor CXCR7. Proc. Natl. Acad. Sci. U.S.A. 107 (2010), 628–632, 10.1073/pnas.0912852107.
Okinaga, S., Slattery, D., Humbles, A., Zsengeller, Z., Morteau, O., Kinrade, M.B., et al. C5L2, a nonsignaling C5A binding protein. Biochemistry 42 (2003), 9406–9415, 10.1021/bi034489v.
de Lau, W., Barker, N., Low, T.Y., Koo, B.-K., Li, V.S.W., Teunissen, H., et al. Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling. Nat. News 476 (2011), 293–297, 10.1038/nature10337.
Cao, W., Luttrell, L.M., Medvedev, A.V., Pierce, K.L., Daniel, K.W., Dixon, T.M., et al. Direct binding of activated c-Src to the beta 3-adrenergic receptor is required for MAP kinase activation. J. Biol. Chem. 275 (2000), 38131–38134, 10.1074/jbc.C000592200.
Al-Sabah, S., Al-Fulaij, M., Shaaban, G., Ahmed, H.A., Mann, R.J., Donnelly, D., et al. The GIP receptor displays higher basal activity than the GLP-1 receptor but does not recruit GRK2 or arrestin3 effectively. PLoS One, 9, 2014, e106890, 10.1371/journal.pone.0106890.
Zhang, H., Han, G.W., Batyuk, A., Ishchenko, A., White, K.L., Patel, N., et al. Structural basis for selectivity and diversity in angiotensin II receptors. Nature 544 (2017), 327–332, 10.1038/nature22035.
Dupuis, N., Laschet, C., Franssen, D., Szpakowska, M., Gilissen, J., Geubelle, P., et al. Activation of the orphan G protein-coupled receptor GPR27 by surrogate ligands promotes β-arrestin 2 recruitment. Mol. Pharmacol., 91, 2017, 10.1124/mol.116.107714.
Matsumoto, M., Saito, T., Takasaki, J., Kamohara, M., Sugimoto, T., Kobayashi, M., et al. An evolutionarily conserved G-protein coupled receptor family SREB, expressed in the central nervous system. Biochem. Biophys. Res. Commun. 272 (2000), 576–582, 10.1006/bbrc.2000.2829.
Chung, S., Funakoshi, T., Civelli, O., Orphan GPCR research. Br. J. Pharmacol. 153:Suppl 1 (2008), S339–S346, 10.1038/sj.bjp.0707606.
Davenport, A.P., Harmar, A.J., Evolving pharmacology of orphan G-Protein coupled receptors. Br. J. Pharmacol., 2013, 10.1111/bph.12339.
Ahmad, R., Wojciech, S., Jockers, R., Hunting for the function of orphan GPCRs – beyond the search for the endogenous ligand. Br. J. Pharmacol. 172 (2015), 3212–3228.
Roth, B.L., Irwin, J.J., Shoichet, B.K., Discovery of new GPCR ligands to illuminate new biology. Nat. Chem. Biol. 13 (2017), 1143–1151, 10.1038/nchembio.2490.
C.Y. Bowers, History to the discovery of ghrelin. - PubMed - NCBI, Ghrelin. 514 (2012) 3–32. doi:10.1016/B978-0-12-381272-8.00001-5.
Xiang, J., Chun, E., Liu, C., Jing, L., Al-Sahouri, Z., Zhu, L., et al. Successful strategies to determine high-resolution structures of GPCRs. Trends Pharmacol. Sci. 37 (2016), 1055–1069, 10.1016/j.tips.2016.09.009.
Ngo, T., Ilatovskiy, A.V., Stewart, A.G., Coleman, J.L.J., McRobb, F.M., Riek, R.P., et al. Orphan receptor ligand discovery by pickpocketing pharmacological neighbors. Nat. Chem. Biol. 13 (2017), 235–242, 10.1038/nchembio.2266.
Huang, X.-P., Karpiak, J., Kroeze, W.K., Zhu, H., Chen, X., Moy, S.S., et al. Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65. Nature, 2015, 10.1038/nature15699.
Lin, H., Sassano, M.F., Roth, B.L., Shoichet, B.K., A pharmacological organization of G protein–coupled receptors. Nat. Methods 10 (2013), 140–146, 10.1038/nmeth.2324.
Stockert, J.A., Devi, L.A., Advancements in therapeutically targeting orphan GPCRs. Front. Pharmacol., 6, 2015, 100, 10.3389/fphar.2015.00100.
Ngo, T., Kufareva, I., Coleman, J.L.J., Graham, R.M., Abagyan, R., Smith, N.J., Identifying ligands at orphan GPCRs: current status using structure-based approaches. Br. J. Pharmacol., 2016, 10.1111/bph.13452.
Kenakin, T., Functional selectivity and biased receptor signaling. J. Pharmacol. Exp. Ther. 336 (2011), 296–302, 10.1124/jpet.110.173948.
Kenakin, T.P., Cellular assays as portals to seven-transmembrane receptor-based drug discovery. Nat. Rev. Drug Discov. 8 (2009), 617–626, 10.1038/nrd2838.
Kenakin, T., Kenakin, C., Watson, V., Muniz-Medina, A., Christopoulos, S., Novick, A simple method for quantifying functional selectivity and agonist bias. ACS Chem. Neurosci. 3 (2012), 193–203, 10.1021/cn200111m.
Hutchings, C.J., Koglin, M., Olson, W.C., Marshall, F.H., Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat. Rev. Drug Discov. 16 (2017), 1–24, 10.1038/nrd.2017.91.
Hutchings, C.J., Cseke, G., Osborne, G., Woolard, J., Zhukov, A., Koglin, M., et al. Monoclonal anti-β1-adrenergic receptor antibodies activate G protein signaling in the absence of β-arrestin recruitment. MAbs. 6 (2014), 246–261, 10.4161/mabs.27226.
Staus, D.P., Wingler, L.M., Strachan, R.T., Rasmussen, S.G.F., Pardon, E., Ahn, S., et al. Regulation of beta-2-adrenergic receptor function by conformationally selective single-domain intrabodies. Mol. Pharmacol. 85 (2013), 472–481, 10.1124/mol.113.089516.
O'Callaghan, K., Kuliopulos, A., Covic, L., Turning receptors on and off with intracellular pepducins: new insights into G-protein-coupled receptor drug development. J. Biol. Chem. 287 (2012), 12787–12796, 10.1074/jbc.R112.355461.
Li, J., Hand, L.E., Meng, Q.-J., Loudon, A.S.I., Bechtold, D.A., GPR50 interacts with TIP60 to modulate glucocorticoid receptor signalling. PLoS One, 6, 2011, e23725, 10.1371/journal.pone.0023725.
Daulat, A.M., Maurice, P., Froment, C., Guillaume, J.-L., Broussard, C., Monsarrat, B., et al. Purification and identification of G protein-coupled receptor protein complexes under native conditions. Mol. Cell Proteomics 6 (2007), 835–844, 10.1074/mcp.M600298-MCP200.
Bergmayr, C., Thurner, P., Keuerleber, S., Kudlacek, O., Nanoff, C., Freissmuth, M., et al. Recruitment of a cytoplasmic chaperone relay by the A2A adenosine receptor. J. Biol. Chem. 288 (2013), 28831–28844, 10.1074/jbc.M113.464776.
Mattheus, T., Kukla, K., Zimmermann, T., Tenzer, S., Lutz, B., Cell type-specific tandem affinity purification of the mouse hippocampal CB1 receptor-associated proteome. J. Proteome Res. 15 (2016), 3585–3601, 10.1021/acs.jproteome.6b00339.
Daulat, A., Maurice, P., Jockers, R., Techniques for the discovery of GPCR-associated protein complexes. Methods Enzymol. 521 (2013), 329–345, 10.1016/B978-0-12-391862-8.00018-1.
Maurice, P., Daulat, A.M., Broussard, C., Mozo, J., Clary, G., Hotellier, F., et al. A generic approach for the purification of signaling complexes that specifically interact with the carboxyl-terminal domain of G protein-coupled receptors. Mol. Cell Proteomics 7 (2008), 1556–1569, 10.1074/mcp.M700435-MCP200.
Chruscinski, A.J., Rohrer, D.K., Schauble, E., Desai, K.H., Bernstein, D., Kobilka, B.K., et al. Targeted disruption of the beta2 adrenergic receptor gene. J. Biol. Chem. 274 (1999), 16694–16700.
Smit, M.J., Vischer, H.F., Bakker, R.A., Jongejan, A., Timmerman, H., Pardo, L., et al. Pharmacogenomic and structural analysis of constitutive g protein-coupled receptor activity. Annu. Rev. Pharmacol. Toxicol. 47 (2007), 53–87, 10.1146/annurev.pharmtox.47.120505.105126.
Bond, R.A., Ijzerman, A.P., Recent developments in constitutive receptor activity and inverse agonism, and their potential for GPCR drug discovery. Trends Pharmacol. Sci. 27 (2006), 92–96, 10.1016/j.tips.2005.12.007.
Civelli, O., Reinscheid, R.K., Zhang, Y., Wang, Z., Fredriksson, R., Fredriksson, R., et al. G protein-coupled receptor deorphanizations. Annu. Rev. Pharmacol. Toxicol. 53 (2013), 127–146, 10.1146/annurev-pharmtox-010611-134548.
Deng, H.K., Unutmaz, D., KewalRamani, V.N., Littman, D.R., Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature 388 (1997), 296–300, 10.1038/40894.
Kiene, M., Rethi, B., Jansson, M., Dillon, S., Lee, E., Lantto, R., et al. Toll-like receptor 3 signalling up-regulates expression of the HIV Co-receptor G-protein coupled receptor 15 on human CD4+ T Cells. PLoS One, 9, 2014, e88195, 10.1371/journal.pone.0088195.
Riddick, N.E., Wu, F., Matsuda, K., Whitted, S., Ourmanov, I., Goldstein, S., et al. Simian immunodeficiency virus sivagm efficiently utilizes non-CCR5 entry pathways in african green monkey lymphocytes: potential role for GPR15 and CXCR6 as viral coreceptors. J. Virol. 90 (2016), 2316–2331, 10.1128/JVI.02529-15.
Kim, S.V., Xiang, W.V., Kwak, C., Yang, Y., Lin, X.W., Ota, M., et al. GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science 340 (2013), 1456–1459, 10.1126/science.1237013.
Lahl, K., Sweere, J., Pan, J., Butcher, E., Orphan chemoattractant receptor GPR15 mediates dendritic epidermal T-cell recruitment to the skin. Eur. J. Immunol. 44 (2014), 2577–2581, 10.1002/eji.201444628.
Konkel, J.E., Zhang, D., Zanvit, P., Chia, C., Zangarle-Murray, T., Jin, W., et al. Transforming growth factor-β signaling in regulatory T cells controls T Helper-17 cells and tissue-specific immune responses. Immunity 46 (2017), 660–674, 10.1016/j.immuni.2017.03.015.
Fischer, A., Zundler, S., Atreya, R., Rath, T., Voskens, C., Hirschmann, S., et al. Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut 65 (2016), 1642–1664, 10.1136/gutjnl-2015-310022.
Suply, T., Hannedouche, S., Carte, N., Li, J., Grosshans, B., Schaefer, M., et al. A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia. Sci. Signaling, 10, 2017, 10.1126/scisignal.aal0180.
Ocón, B., Pan, J., Dinh, T.T., Chen, W., Ballet, R., Bscheider, M., et al. A mucosal and cutaneous chemokine ligand for the lymphocyte chemoattractant receptor GPR15. Front. Immunol., 8, 2017, 705, 10.3389/fimmu.2017.01111.
Milligan, G., Orthologue selectivity and ligand bias: translating the pharmacology of GPR35. Trends Pharmacol. Sci. 32 (2011), 317–325, 10.1016/j.tips.2011.02.002.
Wang, J., Simonavicius, N., Wu, X., Swaminath, G., Reagan, J., Tian, H., et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J. Biol. Chem. 281 (2006), 22021–22028, 10.1074/jbc.M603503200.
Milligan, G., G protein-coupled receptors not currently in the spotlight: free fatty acid receptor 2 and GPR35. Br. J. Pharmacol., 172, 2017, 5744, 10.1111/bph.14042.
Okumura, S.-I., Baba, H., Kumada, T., Nanmoku, K., Nakajima, H., Nakane, Y., et al. Cloning of a G-protein-coupled receptor that shows an activity to transform NIH3T3 cells and is expressed in gastric cancer cells. Cancer Sci. 95 (2004), 131–135.
Guo, J., Williams, D.J., Puhl, H.L., Ikeda, S.R., Inhibition of N-type calcium channels by activation of GPR35, an orphan receptor, heterologously expressed in rat sympathetic neurons. J. Pharmacol. Exp. Ther. 324 (2008), 342–351, 10.1124/jpet.107.127266.
Jenkins, L., Alvarez Curto, E., Campbell, K., de Munnik, S., Canals, M., Schlyer, S., et al. Agonist activation of the G protein-coupled receptor GPR35 involves transmembrane domain III and is transduced via Gα13 and β-arrestin-2. Br. J. Pharmacol. 162 (2011), 733–748, 10.1111/j.1476-5381.2010.01082.x.
Kuc, D., Zgrajka, W., Parada-Turska, J., Urbanik-Sypniewska, T., Turski, W.A., Micromolar concentration of kynurenic acid in rat small intestine. Amino Acids 35 (2008), 503–505, 10.1007/s00726-007-0631-z.
Maravillas-Montero, J.L., Burkhardt, A.M., Hevezi, P.A., Carnevale, C.D., Smit, M.J., Zlotnik, A., Cutting edge: GPR35/CXCR8 is the receptor of the mucosal chemokine CXCL17. J. Immunol. 194 (2015), 29–33, 10.4049/jimmunol.1401704.
Guo, Y.J., Zhou, Y.J., Yang, X.L., Shao, Z.M., Ou, Z.L., The role and clinical significance of the CXCL17-CXCR8 (GPR35) axis in breast cancer. Biochem. Biophys. Res. Commun. 493 (2017), 1159–1167, 10.1016/j.bbrc.2017.09.113.
Park, S.-J., Lee, S.-J., Nam, S.-Y., Im, D.-S., GPR35 mediates lodoxamide-induced migration inhibitory response but not CXCL17-induced migration stimulatory response in THP-1 cells; is GPR35 a receptor for CXCL17?. Br. J. Pharmacol., 174, 2017, S17, 10.1111/bph.14082.
Hu, L.A., Tang, P.M., Eslahi, N.K., Zhou, T., Barbosa, J., Liu, Q., Identification of surrogate agonists and antagonists for orphan G-protein-coupled receptor GPR139. J. Biomol. Screen 14 (2009), 789–797, 10.1177/1087057109335744.
Shi, F., Shen, J.K., Chen, D., Fog, K., Thirstrup, K., Hentzer, M., et al. Discovery and SAR of a series of agonists at orphan G protein-coupled receptor 139. ACS Med. Chem. Lett. 2 (2011), 303–306, 10.1021/ml100293q.
Isberg, V., Andersen, K.B., Bisig, C., Dietz, G.P.H., Bräuner-Osborne, H., Gloriam, D.E., Computer-aided discovery of aromatic l-α-amino acids as agonists of the orphan G protein-coupled receptor GPR139. J. Chem. Inf. Model. 54 (2014), 1553–1557, 10.1021/ci500197a.
Liu, C., Bonaventure, P., Lee, G., Nepomuceno, D., Kuei, C., Wu, J., et al. GPR139, an orphan receptor highly enriched in the habenula and septum is activated by the essential amino acids l-tryptophan and l-phenylalanine. Mol. Pharmacol. 88 (2015), 911–925, 10.1124/mol.115.100412.
Dvorak, C.A., Coate, H., Nepomuceno, D., Wennerholm, M., Kuei, C., Lord, B., et al. Identification and SAR of glycine benzamides as potent agonists for the GPR139 receptor. ACS Med. Chem. Lett. 6 (2015), 1015–1018, 10.1021/acsmedchemlett.5b00247.
Shehata, M.A., Nøhr, A.C., Lissa, D., Bisig, C., Isberg, V., Andersen, K.B., et al. Novel agonist bioisosteres and common structure-activity relationships for the orphan G protein-coupled receptor GPR139. Sci. Rep., 6, 2016, 36681, 10.1038/srep36681.
Nøhr, A.C., Jespers, W., Shehata, M.A., Floryan, L., Isberg, V., Andersen, K.B., et al. The GPR139 reference agonists 1a and 7c, and tryptophan and phenylalanine share a common binding site. Sci. Rep., 7, 2017, 1128, 10.1038/s41598-017-01049-z.
Nøhr, A.C., Shehata, M.A., Hauser, A.S., Isberg, V., Mokrosiński, J., Andersen, K.B., et al. The orphan G protein-coupled receptor GPR139 is activated by the peptides: Adrenocorticotropic hormone (ACTH), α-, and β-melanocyte stimulating hormone (α-MSH, and β-MSH), and the conserved core motif HFRW. Neurochem. Int. 102 (2017), 105–113, 10.1016/j.neuint.2016.11.012.
Bayer Andersen, K., Leander Johansen, J., Hentzer, M., Smith, G.P., Dietz, G.P.H., Protection of primary dopaminergic midbrain neurons by GPR139 agonists supports different mechanisms of MPP+ and rotenone toxicity. Front. Cell. Neurosci., 10(80), 2016, 10.3389/fncel.2016.00164.
Millar, R.P., Lu, Z.-L., Pawson, A.J., Flanagan, C.A., Morgan, K., Maudsley, S.R., Gonadotropin-releasing hormone receptors. Endocrine Rev. 25 (2004), 235–275.
D.O. Larco, N.N. Semsarzadeh, M. Cho-Clark, S.K. Mani, T.J. Wu, β-Arrestin 2 Is a Mediator of GnRH-(1-5) Signaling in Immortalized GnRH Neurons, http://Dx.Doi.org/10.1210/en.2013-1286. (n.d.).
Larco, D.O., Cho-Clark, M., Mani, S.K., Wu, T.J., Wu, T.J., The metabolite GnRH-(1-5) inhibits the migration of immortalized GnRH neurons. Endocrinology 154 (2013), 783–795, 10.1210/en.2012-1746.
Cho-Clark, M., Larco, D.O., Semsarzadeh, N.N., Vasta, F., Mani, S.K., Wu, T.J., GnRH-(1-5) transactivates EGFR in Ishikawa human endometrial cells via an orphan G protein-coupled receptor. Mol. Endocrinol. 28 (2014), 80–98, 10.1210/me.2013-1203.
Trivellin, G., Daly, A.F., Faucz, F.R., Yuan, B., Rostomyan, L., Larco, D.O., et al. Gigantism and acromegaly due to Xq26 microduplications and GPR101Mutation. New England J. Med. 371 (2014), 2363–2374, 10.1056/NEJMoa1408028.
Gomes, I., Aryal, D.K., Wardman, J.H., Gupta, A., Gagnidze, K., Rodriguiz, R.M., et al. GPR171 is a hypothalamic G protein-coupled receptor for BigLEN, a neuropeptide involved in feeding. Proc. Natl. Acad. Sci. U.S.A. 110 (2013), 16211–16216, 10.1073/pnas.1312938110.
Gomes, I., Bobeck, E.N., Margolis, E.B., Gupta, A., Sierra, S., Fakira, A.K., et al. Identification of GPR83 as the receptor for the neuroendocrine peptide PEN. Sci. Signaling, 9, 2016, ra43-ra43, 10.1126/scisignal.aad0694.
Wardman, J.H., Berezniuk, I., Di, S., Tasker, J.G., Fricker, L.D., ProSAAS-derived peptides are colocalized with neuropeptide Y and function as neuropeptides in the regulation of food intake. PLoS One, 6, 2011, e28152, 10.1371/journal.pone.0028152.
Brézillon, S., Detheux, M., Parmentier, M., Hökfelt, T., Hurd, Y.L., Distribution of an orphan G-protein coupled receptor (JP05) mRNA in the human brain. Brain Res. 921 (2001), 21–30.
Müller, T.D., Müller, A., Yi, C.-X., Habegger, K.M., Meyer, C.W., Gaylinn, B.D., et al. The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms. Nat. Commun., 4, 2013, 3438, 10.1038/ncomms2968.
Müller, A., Berkmann, J.C., Scheerer, P., Biebermann, H., Kleinau, G., Insights into basal signaling regulation, oligomerization, and structural organization of the human G-Protein coupled receptor 83. PLoS One, 11, 2016, e0168260, 10.1371/journal.pone.0168260.
Wardman, J.H., Gomes, I., Bobeck, E.N., Stockert, J.A., Kapoor, A., Bisignano, P., et al. Identification of a small-molecule ligand that activates the neuropeptide receptor GPR171 and increases food intake. Sci. Signalling, 9, 2016, ra55-ra55, 10.1126/scisignal.aac8035.
Bobeck, E.N., Gomes, I., Pena, D., Cummings, K.A., Clem, R.L., Mezei, M., et al. The BigLEN-GPR171 peptide receptor system within the basolateral amygdala regulates anxiety-like behavior and contextual fear conditioning. Neuropsychopharmacology 42 (2017), 2527–2536, 10.1038/npp.2017.79.
Dho, S.H., Lee, K.-P., Jeong, D., Kim, C.-J., Chung, K.-S., Kim, J.Y., et al. GPR171 expression enhances proliferation and metastasis of lung cancer cells. Oncotarget 7 (2016), 7856–7865, 10.18632/oncotarget.6856.
Jolly, S., Bazargani, N., Quiroga, A.C., Pringle, N.P., Attwell, D., Richardson, W.D., et al. G protein-coupled receptor 37-like 1 modulates astrocyte glutamate transporters and neuronal NMDA receptors and is neuroprotective in ischemia. Glia 66 (2018), 47–61, 10.1002/glia.23198.
Valdenaire, O., Giller, T., Breu, V., Ardati, A., Schweizer, A., Richards, J.G., A new family of orphan G protein-coupled receptors predominantly expressed in the brain. FEBS Lett. 424 (1998), 193–196, 10.1016/S0014-5793(98)00170-7.
Imai, Y., Soda, M., Inoue, H., Hattori, N., Mizuno, Y., Takahashi, R., An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105 (2001), 891–902, 10.1016/S0092-8674(01)00407-X.
Murakami, T., Shoji, M., Imai, Y., Inoue, H., Kawarabayashi, T., Matsubara, E., et al. Pael-R is accumulated in Lewy bodies of Parkinson's disease. Ann. Neurol. 55 (2004), 439–442, 10.1002/ana.20064.
Zeng, Z., Su, K., Kyaw, H., Li, Y., A novel endothelin receptor type-B-like gene enriched in the brain. Biochem. Biophys. Res. Commun. 233 (1997), 559–567, 10.1006/bbrc.1997.6408.
Coleman, J.L.J., Ngo, T., Schmidt, J., Mrad, N., Liew, C.K., Jones, N.M., et al. Metalloprotease cleavage of the N terminus of the orphan G protein-coupled receptor GPR37L1 reduces its constitutive activity. Sci. Signaling, 9, 2016, ra36-ra36, 10.1126/scisignal.aad1089.
Rezgaoui, M., The neuropeptide head activator is a high-affinity ligand for the orphan G-protein-coupled receptor GPR37. J. Cell Sci. 119 (2006), 542–549, 10.1242/jcs.02766.
Bodenmüller, H., Schaller, H.C., Conserved amino acid sequence of a neuropeptide, the head activator, from coelenterates to humans. Nature 293 (1981), 579–580.
Gandía, J., Fernández-Dueñas, V., Morató X., Caltabiano, G., González-Muñiz, R., Pardo, L., et al. The Parkinson's disease-associated GPR37 receptor-mediated cytotoxicity is controlled by its intracellular cysteine-rich domain. J. Neurochem. 125 (2013), 362–372, 10.1111/jnc.12196.
Dunham, J.H., Meyer, R.C., Garcia, E.L., Hall, R.A., GPR37 surface expression enhancement via N-terminal truncation or protein-protein interactions. Biochemistry-Us 48 (2009), 10286–10297, 10.1021/bi9013775.
Southern, C., Cook, J.M., Neetoo-Isseljee, Z., Taylor, D.L., Kettleborough, C.A., Merritt, A., et al. Screening -arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors. J. Biomol. Screen, 2013, 10.1177/1087057113475480.
Meyer, R.C., Giddens, M.M., Schaefer, S.A., Hall, R.A., GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin. Proc. Natl. Acad. Sci. US..A. 110 (2013), 9529–9534, 10.1073/pnas.1219004110.
Hollenberg, M.D., Compton, S.J., International union of pharmacology. XXVIII. Proteinase-activated receptors. Pharmacol. Rev. 54 (2002), 203–217, 10.1016/S0006-2952(00)00460-3.
Ossovskaya, V.S., Bunnett, N.W., Protease-activated receptors: contribution to physiology and disease. Physiol. Rev. 84 (2004), 579–621, 10.1152/physrev.00028.2003.—Proteases.
Araç D., Boucard, A.A., Bolliger, M.F., Nguyen, J., Soltis, S.M., Südhof, T.C., et al. A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis. EMBO J. 31 (2012), 1364–1378, 10.1038/emboj.2012.26.
Liebscher, I., Schöneberg, T., Prömel, S., Progress in demystification of adhesion G protein-coupled receptors. Biol. Chem. 394 (2013), 937–950, 10.1515/hsz-2013-0109.
Liebscher, I., Schön, J., Petersen, S.C., Fischer, L., Auerbach, N., Demberg, L.M., et al. A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. Cell Rep. 9 (2014), 2018–2026, 10.1016/j.celrep.2014.11.036.
Mogha, A., Benesh, A.E., Patra, C., Engel, F.B., Schöneberg, T., Liebscher, I., et al. Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation. J. Neurosci. 33 (2013), 17976–17985, 10.1523/JNEUROSCI.1809-13.2013.
Petersen, S.C., Luo, R., Liebscher, I., Giera, S., Jeong, S.-J., Mogha, A., et al. The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211. Neuron 85 (2015), 755–769, 10.1016/j.neuron.2014.12.057.
Demberg, L.M., Rothemund, S., Schöneberg, T., Liebscher, I., Identification of the tethered peptide agonist of the adhesion G protein-coupled receptor GPR64/ADGRG2. Biochem. Biophys. Res. Commun. 464 (2015), 743–747, 10.1016/j.bbrc.2015.07.020.
Wilde, C., Fischer, L., Lede, V., Kirchberger, J., Rothemund, S., Schöneberg, T., et al. The constitutive activity of the adhesion GPCR GPR114/ADGRG5 is mediated by its tethered agonist. FASEB J. 30 (2016), 666–673, 10.1096/fj.15-276220.
Demberg, L.M., Winkler, J., Wilde, C., Simon, K.-U., Schön, J., Rothemund, S., et al. Activation of adhesion G protein-coupled receptors: agonist specificity of stachel sequence-derived peptides. J. Biol. Chemstry. 292 (2017), 4383–4394, 10.1074/jbc.M116.763656.
Küffer, A., Lakkaraju, A.K.K., Mogha, A., Petersen, S.C., Airich, K., Doucerain, C., et al. The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. Nat. News 536 (2016), 464–468, 10.1038/nature19312.
Ignatov, A., Robert, J., Gregory Evans, C., Schaller, H.C., RANTES stimulates Ca 2+ mobilization and inositol trisphosphate (IP3) formation in cells transfected with G protein-coupled receptor 75. Br. J. Pharmacol. 149 (2006), 490–497, 10.1038/sj.bjp.0706909.
Liu, B., Hassan, Z., Amisten, S., King, A.J., Bowe, J.E., Huang, G.C., et al. The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis. Diabetologia 56 (2013), 2467–2476, 10.1007/s00125-013-3022-x.
Garcia, V., Gilani, A., Shkolnik, B., Pandey, V., Zhang, F.F., Dakarapu, R., et al. 20-HETE signals through G-protein-coupled receptor GPR75 (Gq) to affect vascular function and trigger hypertension. Circ. Res. 120 (2017), 1776–1788, 10.1161/CIRCRESAHA.116.310525.
Hoopes, S.L., Garcia, V., Edin, M.L., Schwartzman, M.L., Zeldin, D.C., Vascular actions of 20-HETE. Prostaglandins Other Lipid Mediat. 120 (2015), 9–16, 10.1016/j.prostaglandins.2015.03.002.
Yosten, G.L.C., Redlinger, L.J., Samson, W.K., Evidence for an interaction of neuronostatin with the orphan G protein-coupled receptor, GPR107, AJP: regulatory. Integr. Comp. Physiol. 303 (2012), R941–R949, 10.1152/ajpregu.00336.2012.
Samson, W.K., Zhang, J.V., Avsian-Kretchmer, O., Cui, K., Yosten, G.L.C., Klein, C., et al. Neuronostatin encoded by the somatostatin gene regulates neuronal, cardiovascular, and metabolic functions. J. Biol. Chem. 283 (2008), 31949–31959, 10.1074/jbc.M804784200.
Salvatori, A.S., Elrick, M.M., Samson, W.K., Corbett, J.A., Yosten, G.L.C., Neuronostatin inhibits glucose-stimulated insulin secretion via direct action on the pancreatic α-cell. AJP Endocrinol. Metab. 306 (2014), E1257–63, 10.1152/ajpendo.00599.2013.
Elrick, M.M., Samson, W.K., Corbett, J.A., Salvatori, A.S., Stein, L.M., Kolar, G.R., et al. Neuronostatin acts via GPR107 to increase cAMP-independent PKA phosphorylation and proglucagon mRNA accumulation in pancreatic α-cells. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310 (2016), R143–55, 10.1152/ajpregu.00369.2014.
Yosten, G.L.C., Kolar, G.R., Redlinger, L.J., Samson, W.K., Evidence for an interaction between proinsulin C-peptide and GPR146. J. Endocrinol. 218 (2013), B1–8.
Luppi, P., Cifarelli, V., Wahren, J., C-peptide and long-term complications of diabetes. Pediatr. Diabetes 12 (2011), 276–292, 10.1111/j.1399-5448.2010.00729.x.
Huang, H., Zhang, N., Xiong, Q., Chen, R., Zhang, C., Wang, N., et al. Elimination of GPR146-mediated antiviral function through IRF3/HES1-signalling pathway. Immunology 152 (2017), 102–114, 10.1111/imm.12752.
Ye, R.D., Boulay, F., Wang, J.M., Dahlgren, C., Gerard, C., Parmentier, M., et al. International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol. Rev. 61 (2009), 119–161, 10.1124/pr.109.001578.
Chiang, N., Serhan, C.N., Dahlén, S.-E., Drazen, J.M., Hay, D.W.P., Rovati, G.E., et al. The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacol. Rev. 58 (2006), 463–487, 10.1124/pr.58.3.4.
Hanson, J., Ferreirós, N., Pirotte, B., Geisslinger, G., Offermanns, S., Offermanns, S., Heterologously expressed formyl peptide receptor 2 (FPR2/ALX) does not respond to lipoxin A4. Biochem. Pharmacol. 85 (2013), 1795–1802, 10.1016/j.bcp.2013.04.019.
Forsman, H., Onnheim, K., Andreasson, E., Dahlgren, C., What formyl peptide receptors, if any, are triggered by compound 43 and lipoxin A4?. Scand. J. Immunol. 74 (2011), 227–234, 10.1111/j.1365-3083.2011.02570.x.
Forsman, H., Dahlgren, C., Lipoxin A(4) metabolites/analogues from two commercial sources have no effects on TNF-alpha-mediated priming or activation through the neutrophil formyl peptide receptors. Scand. J. Immunol. 70 (2009), 396–402, 10.1111/j.1365-3083.2009.02311.x.
Planagumà A., Domenech, T., Jover, I., Ramos, I., Sentellas, S., Malhotra, R., et al. Lack of activity of 15-epi-lipoxin A₄ on FPR2/ALX and CysLT1 receptors in interleukin-8-driven human neutrophil function. Clin. Exp. Immunol. 173 (2013), 298–309, 10.1111/cei.12110.
Bae, Y.-S., Park, J.C., He, R., Ye, R.D., Kwak, J.-Y., Suh, P.-G., et al. Differential signaling of formyl peptide receptor-like 1 by Trp-Lys-Tyr-Met-Val-Met-CONH2 or lipoxin A4 in human neutrophils. Mol. Pharmacol. 64 (2003), 721–730, 10.1124/mol.64.3.721.
Bäck, M., Powell, W.S., Dahlén, S.-E., Drazen, J.M., Evans, J.F., Serhan, C.N., et al. Update on leukotriene, lipoxin and oxoeicosanoid receptors: IUPHAR Review 7. Br. J. Pharmacol. 171 (2014), 3551–3574, 10.1111/bph.12665.
Serhan, C.N., Gotlinger, K., Hong, S., Arita, M., Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis. Prostaglandins Other Lipid Mediat. 73 (2004), 155–172.
Serhan, C.N., Pro-resolving lipid mediators are leads for resolution physiology. Nat. News 510 (2014), 92–101, 10.1038/nature13479.
Arita, M., Bianchini, F., Aliberti, J., Sher, A., Chiang, N., Hong, S., et al. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201 (2005), 713–722, 10.1084/jem.20042031.
Wittamer, V., Franssen, J.-D., Vulcano, M., Mirjolet, J.-F., Le Poul, E., Migeotte, I., et al. Specific recruitment of antigen-presenting cells by chemerin, a novel processed ligand from human inflammatory fluids. J. Exp. Med. 198 (2003), 977–985, 10.1084/jem.20030382.
Krishnamoorthy, S., Recchiuti, A., Chiang, N., Yacoubian, S., Lee, C.-H., Yang, R., et al. Resolvin D1 binds human phagocytes with evidence for proresolving receptors. Proc. Natl. Acad. Sci. U.S.A. 107 (2010), 1660–1665, 10.1073/pnas.0907342107.
Chiang, N., Fredman, G., Bäckhed, F., Oh, S.F., Vickery, T., Schmidt, B.A., et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nat. News 484 (2012), 524–528, 10.1038/nature11042.
Bondue, B., Wittamer, V., Parmentier, M., Chemerin and its receptors in leukocyte trafficking, inflammation and metabolism. Cytokine Growth Factor Rev. 22 (2011), 331–338, 10.1016/j.cytogfr.2011.11.004.
Chen, Y., Wu, H., Wang, S., Koito, H., Li, J., Ye, F., et al. The oligodendrocyte-specific G protein–coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nat. Neurosci. 12 (2009), 1398–1406, 10.1038/nn.2410.
Ciana, P., Fumagalli, M., Trincavelli, M.L., Verderio, C., Rosa, P., Lecca, D., et al. The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J. 25 (2006), 4615–4627, 10.1038/sj.emboj.7601341.
Benned-Jensen, T., Rosenkilde, M.M., Distinct expression and ligand-binding profiles of two constitutively active GPR17 splice variants. Br. J. Pharmacol. 159 (2010), 1092–1105, 10.1111/j.1476-5381.2009.00633.x.
Qi, A.D., Harden, T.K., Nicholas, R.A., Is GPR17 a P2Y/Leukotriene receptor? Examination of uracil nucleotides, nucleotide-sugars, and cysteinyl-leukotrienes as agonists of GPR17. J. Pharmacol. Exp. Ther. 347 (2013), 38–46, 10.1124/jpet.113.207647.
Köse, M., Ritter, K., Thiemke, K., Gillard, M., Kostenis, E., Müller, C.E., Development of [3H]2-Carboxy-4,6-dichloro-1H-indole-3-propionic Acid ([3H]PSB-12150): a useful tool for studying GPR17. ACS Med. Chem. Lett. 5 (2014), 326–330, 10.1021/ml400399f.
Hennen, S., Wang, H., Peters, L., Merten, N., Simon, K., Spinrath, A., et al. Decoding signaling and function of the orphan G protein-coupled receptor GPR17 with a small-molecule agonist. Sci. Signaling, 6, 2013, ra93-ra93, 10.1126/scisignal.2004350.
Mogha, A., D'Rozario, M., Monk, K.R., G protein-coupled receptors in myelinating Glia. Trends Pharmacol. Sci. 37 (2016), 977–987, 10.1016/j.tips.2016.09.002.
Simon, K., Merten, N., Schröder, R., Hennen, S., Preis, P., Schmitt, N.-K., et al. The orphan receptor gpr17 is unresponsive to uracil-nucleotides and cysteinyl-leukotrienES. Mol. Pharmacol., 91, 2017, 10.1124/mol.116.107904.
Lecca, D., Trincavelli, M.L., Gelosa, P., Sironi, L., Ciana, P., Fumagalli, M., et al. The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. PLoS One, 3, 2008, e3579, 10.1371/journal.pone.0003579.
Ren, H., Orozco, I.J., Su, Y., Suyama, S., Gutiérrez-Juárez, R., Horvath, T.L., et al. FoxO1 target Gpr17 activates AgRP neurons to regulate food intake. Cell 149 (2012), 1314–1326, 10.1016/j.cell.2012.04.032.
Marschallinger, J., Schäffner, I., Klein, B., Gelfert, R., Rivera, F.J., Illes, S., et al. Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug. Nat. Commun., 6, 2015, 8466, 10.1038/ncomms9466.
Caldwell, M.D., Hu, S.S.-J., Viswanathan, S., Bradshaw, H., Kelly, M.E., Straiker, A., A GPR18-based signalling system regulates IOP in murine eye. Br. J. Pharmacol. 169 (2013), 834–843, 10.1111/bph.12136.
Qin, Y., Verdegaal, E.M.E., Siderius, M., Bebelman, J.P., Smit, M.J., Leurs, R., et al. Quantitative expression profiling of G protein-coupled receptors (GPCRs) in metastatic melanoma: the constitutively active orphan GPCR GPR18 as novel drug target. Pigment Cell Melanoma Res., 24, 2010, 218, 10.1111/j.1755-148X.2010.00781.x.
Takenouchi, R., Inoue, K., Kambe, Y., Miyata, A., N-arachidonoyl glycine induces macrophage apoptosis via GPR18. Biochem. Biophys. Res. Commun. 418 (2012), 366–371, 10.1016/j.bbrc.2012.01.027.
Kohno, M., Hasegawa, H., Inoue, A., Muraoka, M., Miyazaki, T., Oka, K., et al. Identification of N-arachidonylglycine as the endogenous ligand for orphan G-protein-coupled receptor GPR18. Biochem. Biophys. Res. Commun. 347 (2006), 827–832, 10.1016/j.bbrc.2006.06.175.
Lu, V.B., Puhl, H.L., Ikeda, S.R., N-Arachidonyl glycine does not activate G protein-coupled receptor 18 signaling via canonical pathways. Mol. Pharmacol. 83 (2013), 267–282, 10.1124/mol.112.081182.
Finlay, D.B., Joseph, W.R., Grimsey, N.L., Glass, M., GPR18 undergoes a high degree of constitutive trafficking but is unresponsive to N-Arachidonoyl Glycine. Peer J., 4, 2016, e1835, 10.7717/peerj.1835.
Christiansen, B., Hansen, K.B., Wellendorph, P., Brauner-Osborne, H., Pharmacological characterization of mouse GPRC6A, an L-alpha-amino-acid receptor modulated by divalent cations. Br. J. Pharmacol. 150 (2007), 798–807, 10.1038/sj.bjp.0707121.
Pi, M., Wu, Y., Lenchik, N.I., Gerling, I., Quarles, L.D., GPRC6A mediates the effects of L-arginine on insulin secretion in mouse pancreatic islets. Endocrinology 153 (2012), 4608–4615, 10.1210/en.2012-1301.
Pi, M., Parrill, A.L., Quarles, L.D., GPRC6A mediates the non-genomic effects of steroids. J. Biol. Chem. 285 (2010), 39953–39964, 10.1074/jbc.M110.158063.
Pi, M., Faber, P., Ekema, G., Jackson, P.D., Ting, A., Wang, N., et al. Identification of a novel extracellular cation-sensing G-protein-coupled receptor. J. Biol. Chem. 280 (2005), 40201–40209, 10.1074/jbc.M505186200.
Sumara, G., Sumara, O., Chang, H., Smith, C.E., Hermo, L., Suarez, S., et al. Endocrine regulation of male fertility by the skeleton. Cell 144 (2011), 796–809, 10.1016/j.cell.2011.02.004.
Pi, M., Wu, Y., Quarles, L.D., GPRC6A mediates responses to osteocalcin in β-cells in vitro and pancreas in vivo. J. Bone Miner. Res. 26 (2011), 1680–1683, 10.1002/jbmr.390.
Rueda, P., Harley, E., Lu, Y., Stewart, G.D., Fabb, S., Diepenhorst, N., et al. Murine GPRC6A mediates cellular responses to L-amino acids, but not osteocalcin variants. PLoS One, 11, 2016, e0146846, 10.1371/journal.pone.0146846.
Liu, R., Wong, W., Ijzerman, A.P., Human G protein-coupled receptor studies in Saccharomyces cerevisiae. Biochem. Pharmacol., 2016, 1–13, 10.1016/j.bcp.2016.02.010.
Fiore, S., Maddox, J.F., Perez, H.D., Serhan, C.N., Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor. J. Exp. Med. 180 (1994), 253–260.
Bondue, B., Wittamer, V., Parmentier, M., Chemerin and its receptors in leukocyte trafficking, inflammation and metabolism. Cytokine Growth Factor Rev. 22 (2011), 331–338, 10.1016/j.cytogfr.2011.11.004.