Table 1 lists a number of putative GPCRs identified by NC-IUPHAR [27], for which preliminary evidence for an endogenous ligand has been published, or for which there exists a potential link to a disease, or disorder. These GPCRs have recently been reviewed in detail [18]. The GPCRs in Table 1 are all Class A, rhodopsin-like GPCRs. Class A orphan GPCRs not listed in Table 1 are putative GPCRs with as-yet unidentified endogenous ligands.

Table 1: Class A orphan GPCRs with putative endogenous ligands

GPR3	GPR4	GPR6	GPR12	GPR15	GPR17	GPR20
GPR22	GPR26	GPR31	GPR34	GPR35	GPR37	GPR39
GPR50	GPR63	GPR65	GPR68	GPR75	GPR84	GPR87
GPR88	GPR132	GPR149	GPR161	GPR183	LGR4	LGR5
LGR6	MAS1	MRGPRD	MRGPRX1	MRGPRX2	P2RY10	TAAR2

In addition the orphan receptors GPR18, GPR55 and GPR119 which are reported to respond to endogenous agents analogous to the endogenous cannabinoid ligands have been grouped together (GPR18, GPR55 and GPR119).

* Key recommended reading is highlighted with an asterisk

* Akbari P, Gilani A, Sosina O, Kosmicki JA, Khrimian L, Fang YY, Persaud T, Garcia V, Sun D, Li A et al.. (2021) Sequencing of 640,000 exomes identifies GPR75 variants associated with protection from obesity. Science, 373 (6550). DOI: 10.1126/science.abf8683 [PMID:34210852]

* Hershfinkel M. (2024) Cross-talk between zinc and calcium regulates ion transport: A role for the zinc receptor, ZnR/GPR39. J Physiol, 602 (8): 1579-1594. [PMID:37462604]

* McNeil BD, Pundir P, Meeker S, Han L, Undem BJ, Kulka M, Dong X. (2015) Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions. Nature, 519 (7542): 237-41. [PMID:25517090]

* Wirthgen E, Hoeflich A, Rebl A, Günther J. (2017) Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions. Front Immunol, 8: 1957. [PMID:29379504]

Zhang LY, Jia MR, Sun T. (2018) The roles of special proresolving mediators in pain relief. Rev Neurosci, 29 (6): 645-660. [PMID:29420307]

Zhang Q, Zhao X, Qin S, Xiao Q, Tain Y, Zhang Z, Zhang P, Xu F. (2024) Identification of GPR35-associated metabolic characteristics through LC-MS/MS-based metabolomics and lipidomics. Acta Materia Medica, [Epub]. DOI: 10.15212/AMM-2023-0046

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81. 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 (4): 707-12. [PMID:18466763]

82. Müller A, Kleinau G, Piechowski CL, Müller TD, Finan B, Pratzka J, Grüters A, Krude H, Tschöp M, Biebermann H. (2013) G-protein coupled receptor 83 (GPR83) signaling determined by constitutive and zinc(II)-induced activity. PLoS ONE, 8 (1): e53347. [PMID:23335960]

83. Müller A, Leinweber B, Fischer J, Müller TD, Grüters A, Tschöp MH, Knäuper V, Biebermann H, Kleinau G. (2014) The extracellular N-terminal domain of G-protein coupled receptor 83 regulates signaling properties and is an intramolecular inverse agonist. BMC Res Notes, 7: 913. [PMID:25516095]

84. Nambu H, Fukushima M, Hikichi H, Inoue T, Nagano N, Tahara Y, Nambu T, Ito J, Ogawa Y, Ozaki S et al.. (2011) Characterization of metabolic phenotypes of mice lacking GPR61, an orphan G-protein coupled receptor. Life Sci, 89 (21-22): 765-72. [PMID:21971119]

85. Niedernberg A, Tunaru S, Blaukat A, Ardati A, Kostenis E. (2003) Sphingosine 1-phosphate and dioleoylphosphatidic acid are low affinity agonists for the orphan receptor GPR63. Cell Signal, 15 (4): 435-46. [PMID:12618218]

86. Nikaido Y, Koyama Y, Yoshikawa Y, Furuya T, Takeda S. (2015) Mutation analysis and molecular modeling for the investigation of ligand-binding modes of GPR84. J Biochem, 157 (5): 311-20. [PMID:25425658]

87. No authors listed. (2005) Sphingosylphosphorylcholine and lysophosphatidylcholine are ligands for the G protein-coupled receptor GPR4. (Retraction). J Biol Chem, 280 (52): 43280. [PMID:16498716]

88. Oka S, Ota R, Shima M, Yamashita A, Sugiura T. (2010) GPR35 is a novel lysophosphatidic acid receptor. Biochem Biophys Res Commun, 395 (2): 232-7. [PMID:20361937]

89. Osborn O, Oh da Y, McNelis J, Sanchez-Alavez M, Talukdar S, Lu M, Li P, Thiede L, Morinaga H, Kim JJ et al.. (2012) G protein-coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice. J Clin Invest, 122 (7): 2444-53. [PMID:22653059]

90. Padmanabhan S, Myers AG, Prasad BM. (2009) Constitutively active GPR6 is located in the intracellular compartments. FEBS Lett, 583 (1): 107-12. [PMID:19059244]

91. Pereira JP, Kelly LM, Xu Y, Cyster JG. (2009) EBI2 mediates B cell segregation between the outer and centre follicle. Nature, 460 (7259): 1122-6. [PMID:19597478]

92. Petersen PS, Jin C, Madsen AN, Rasmussen M, Kuhre R, Egerod KL, Nielsen LB, Schwartz TW, Holst B. (2011) Deficiency of the GPR39 receptor is associated with obesity and altered adipocyte metabolism. FASEB J, 25 (11): 3803-14. [PMID:21784784]

93. Pringle KG, Tadros MA, Callister RJ, Lumbers ER. (2011) The expression and localization of the human placental prorenin/renin-angiotensin system throughout pregnancy: roles in trophoblast invasion and angiogenesis?. Placenta, 32 (12): 956-62. [PMID:22018415]

94. Rao A, Herr DR. (2017) G protein-coupled receptor GPR19 regulates E-cadherin expression and invasion of breast cancer cells. Biochim Biophys Acta, 1864 (7): 1318-1327. [PMID:28476646]

95. Rezgaoui M, Süsens U, Ignatov A, Gelderblom M, Glassmeier G, Franke I, Urny J, Imai Y, Takahashi R, Schaller HC. (2006) The neuropeptide head activator is a high-affinity ligand for the orphan G-protein-coupled receptor GPR37. J Cell Sci, 119 (Pt 3): 542-9. [PMID:16443751]

96. Robas N, Mead E, Fidock M. (2003) MrgX2 is a high potency cortistatin receptor expressed in dorsal root ganglion. J Biol Chem, 278 (45): 44400-4. [PMID:12915402]

97. Ruffner H, Sprunger J, Charlat O, Leighton-Davies J, Grosshans B, Salathe A, Zietzling S, Beck V, Therier M, Isken A et al.. (2012) R-Spondin potentiates Wnt/β-catenin signaling through orphan receptors LGR4 and LGR5. PLoS ONE, 7 (7): e40976. [PMID:22815884]

98. Ruiz-Medina J, Ledent C, Valverde O. (2011) GPR3 orphan receptor is involved in neuropathic pain after peripheral nerve injury and regulates morphine-induced antinociception. Neuropharmacology, 61 (1-2): 43-50. [PMID:21352831]

99. Russell JL, Goetsch SC, Aguilar HR, Coe H, Luo X, Liu N, van Rooij E, Frantz DE, Schneider JW. (2012) Regulated expression of pH sensing G Protein-coupled receptor-68 identified through chemical biology defines a new drug target for ischemic heart disease. ACS Chem Biol, 7 (6): 1077-83. [PMID:22462679]

100. Römpler H, Schulz A, Pitra C, Coop G, Przeworski M, Pääbo S, Schöneberg T. (2005) The rise and fall of the chemoattractant receptor GPR33. J Biol Chem, 280 (35): 31068-75. [PMID:15987686]

101. Setoh M, Ishii N, Kono M, Miyanohana Y, Shiraishi E, Harasawa T, Ota H, Odani T, Kanzaki N, Aoyama K et al.. (2014) Discovery of the first potent and orally available agonist of the orphan G-protein-coupled receptor 52. J Med Chem, 57 (12): 5226-37. [PMID:24884590]

102. Seuwen K, Ludwig MG, Wolf RM. (2006) Receptors for protons or lipid messengers or both?. J Recept Signal Transduct Res, 26 (5-6): 599-610. [PMID:17118800]

103. Shinohara T, Harada M, Ogi K, Maruyama M, Fujii R, Tanaka H, Fukusumi S, Komatsu H, Hosoya M, Noguchi Y et al.. (2004) Identification of a G protein-coupled receptor specifically responsive to beta-alanine. J Biol Chem, 279 (22): 23559-64. [PMID:15037633]

104. Sikand P, Dong X, LaMotte RH. (2011) BAM8-22 peptide produces itch and nociceptive sensations in humans independent of histamine release. J Neurosci, 31 (20): 7563-7. [PMID:21593341]

105. Solinski HJ, Gudermann T, Breit A. (2014) Pharmacology and signaling of MAS-related G protein-coupled receptors. Pharmacol Rev, 66 (3): 570-97. [PMID:24867890]

106. Song H, Luo J, Luo W, Weng J, Wang Z, Li B, Li D, Liu M. (2008) Inactivation of G-protein-coupled receptor 48 (Gpr48/Lgr4) impairs definitive erythropoiesis at midgestation through down-regulation of the ATF4 signaling pathway. J Biol Chem, 283 (52): 36687-97. [PMID:18955481]

107. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS et al.. (2013) Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors. J Biomol Screen, 18 (5): 599-609. [PMID:23396314]

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 (4): 1078-87. [PMID:16460680]

109. Suzuki M, Takaishi S, Nagasaki M, Onozawa Y, Iino I, Maeda H, Komai T, Oda T. (2013) Medium-chain Fatty Acid-sensing Receptor, GPR84, Is a Proinflammatory Receptor. J Biol Chem, 288 (15): 10684-91. [PMID:23449982]

110. 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 (3): 861-6. [PMID:17905198]

111. Takeda S, Okada T, Okamura M, Haga T, Isoyama-Tanaka J, Kuwahara H, Minamino N. (2004) The receptor-Galpha fusion protein as a tool for ligand screening: a model study using a nociceptin receptor-Galphai2 fusion protein. J Biochem, 135 (5): 597-604. [PMID:15173198]

112. Taniguchi Y, Tonai-Kachi H, Shinjo K. (2006) Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is an agonist for GPR35. FEBS Lett, 580 (21): 5003-8. [PMID:16934253]

113. Thathiah A, Spittaels K, Hoffmann M, Staes M, Cohen A, Horré K, Vanbrabant M, Coun F, Baekelandt V, Delacourte A, Fischer DF, Pollet D, De Strooper B, Merchiers P. (2009) The orphan G protein-coupled receptor 3 modulates amyloid-beta peptide generation in neurons. Science, 323: 946-951. [PMID:19213921]

114. Tobo A, Tobo M, Nakakura T, Ebara M, Tomura H, Mogi C, Im DS, Murata N, Kuwabara A, Ito S et al.. (2015) Characterization of Imidazopyridine Compounds as Negative Allosteric Modulators of Proton-Sensing GPR4 in Extracellular Acidification-Induced Responses. PLoS ONE, 10 (6): e0129334. [PMID:26070068]

115. Toda N, Hao X, Ogawa Y, Oda K, Yu M, Fu Z, Chen Y, Kim Y, Lizarzaburu M, Lively S et al.. (2013) Potent and Orally Bioavailable GPR142 Agonists as Novel Insulin Secretagogues for the Treatment of Type 2 Diabetes. ACS Med Chem Lett, 4 (8): 790-4. [PMID:24900747]

116. Trivellin G, Daly AF, Faucz FR, Yuan B, Rostomyan L, Larco DO, Schernthaner-Reiter MH, Szarek E, Leal LF, Caberg JH et al.. (2014) Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation. N Engl J Med, 371 (25): 2363-74. [PMID:25470569]

117. Uhlenbrock K, Gassenhuber H, Kostenis E. (2002) Sphingosine 1-phosphate is a ligand of the human gpr3, gpr6 and gpr12 family of constitutively active G protein-coupled receptors. Cell Signal, 14: 941-953. [PMID:12220620]

118. Valdes AM, Spector TD. (2010) The genetic epidemiology of osteoarthritis. Curr Opin Rheumatol, 22 (2): 139-43. [PMID:20090528]

119. Vanti WB, Muglia P, Nguyen T, Cheng R, Kennedy JL, George SR, O'Dowd BF. (2003) Discovery of a null mutation in a human trace amine receptor gene. Genomics, 82: 531-536. [PMID:14559210]

120. Wallrabenstein I, Kuklan J, Weber L, Zborala S, Werner M, Altmüller J, Becker C, Schmidt A, Hatt H, Hummel T et al.. (2013) Human trace amine-associated receptor TAAR5 can be activated by trimethylamine. PLoS ONE, 8 (2): e54950. [PMID:23393561]

121. 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 (31): 22021-8. [PMID:16754668]

122. 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 (45): 34457-64. [PMID:16966319]

123. Wang P, Raja A, Luscombe VB, Bataille CJR, Lucy D, Rogga VV, Greaves DR, Russell AJ. (2024) Development of Highly Potent, G-Protein Pathway Biased, Selective, and Orally Bioavailable GPR84 Agonists. J Med Chem, 67 (1): 110-137. [PMID:38146625]

124. Weng J, Luo J, Cheng X, Jin C, Zhou X, Qu J, Tu L, Ai D, Li D, Wang J, Martin JF, Amendt BA, Liu M. (2008) Deletion of G protein-coupled receptor 48 leads to ocular anterior segment dysgenesis (ASD) through down-regulation of Pitx2. Proc Natl Acad Sci USA, 105 (16): 6081-6. [PMID:18424556]

125. Witte ON, Kabarowski JH, Xu Y, Le LQ, Zhu K. (2005) Retraction. Science, 307 (5707): 206. [PMID:15653487]

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127. Yang LV, Radu CG, Roy M, Lee S, McLaughlin J, Teitell MA, Iruela-Arispe ML, Witte ON. (2007) Vascular abnormalities in mice deficient for the G protein-coupled receptor GPR4 that functions as a pH sensor. Mol Cell Biol, 27 (4): 1334-47. [PMID:17145776]

128. Yasuda H, Hirata S, Inoue K, Mashima H, Ohnishi H, Yoshiba M. (2007) Involvement of membrane-type bile acid receptor M-BAR/TGR5 in bile acid-induced activation of epidermal growth factor receptor and mitogen-activated protein kinases in gastric carcinoma cells. Biochem Biophys Res Commun, 354 (1): 154-9. [PMID:17214962]

129. Ye C, Zhang Z, Wang Z, Hua Q, Zhang R, Xie X. (2014) Identification of a novel small-molecule agonist for human G protein-coupled receptor 3. J Pharmacol Exp Ther, 349 (3): 437-43. [PMID:24633425]

130. Yin H, Chu A, Li W, Wang B, Shelton F, Otero F, Nguyen DG, Caldwell JS, Chen YA. (2009) Lipid G protein-coupled receptor ligand identification using beta-arrestin PathHunter assay. J Biol Chem, 284: 12328-12338. [PMID:19286662]

131. Yosten GL, Kolar GR, Redlinger LJ, Samson WK. (2013) Evidence for an interaction between proinsulin C-peptide and GPR146. J Endocrinol, 218 (2): B1-8. [PMID:23759446]

132. Yu M, Lizarzaburu M, Motani A, Fu Z, Du X, Liu JJ, Jiao X, Lai S, Fan P, Fu A et al.. (2013) Aminopyrazole-Phenylalanine Based GPR142 Agonists: Discovery of Tool Compound and in Vivo Efficacy Studies. ACS Med Chem Lett, 4 (9): 829-34. [PMID:24900757]

133. Zhang LL, Wang JJ, Liu Y, Lu XB, Kuang Y, Wan YH, Chen Y, Yan HM, Fei J, Wang ZG. (2011) GPR26-deficient mice display increased anxiety- and depression-like behaviors accompanied by reduced phosphorylated cyclic AMP responsive element-binding protein level in central amygdala. Neuroscience, 196: 203-14. [PMID:21924326]

134. Zhao P, Sharir H, Kapur A, Cowan A, Geller EB, Adler MW, Seltzman HH, Reggio PH, Heynen-Genel S, Sauer M, Chung TD, Bai Y, Chen W, Caron MG, Barak LS, Abood ME. (2010) Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity. Mol Pharmacol, 78 (4): 560-8. [PMID:20826425]

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Stephen P.H. Alexander Associate Professor in Molecular Pharmacology Life Sciences E Floor University of Nottingham Medical School Nottingham NG7 2UH UK Jim Battey (BB3) National Institute on Deafness and Other Communication Disorders Building 31 Room 3C02 NIH Bethesda MD 20892 USA Helen E. Benson (Past curator) Centre for Discovery Brain Sciences Edinburgh Medical School: Biomedical Sciences Room 338 Hugh Robson Building George Square Edinburgh EH8 9XD UK Richard V. Benya (BB3) University of Illinois Section of Digestive Diseases and Nutrition 840 South Wood Street (M/C 716) Chicago Illinois 60612 USA Tom I. Bonner (Past Core Member) Special Volunteer Office of Science Director NIMH Bethesda MD USA Anthony P. Davenport Experimental Medicine and Immunotherapeutics University of Cambridge Addenbrooke’s Hospital Cambridge UK Khuraijam Dhanachandra Singh Department of Molecular Cardiology Lerner Research Institute The Cleveland Clinic Foundation 9500 Euclid Ave. Cleveland, OH 44195 USA Satoru Eguchi Cardiovascular Research Center Temple University School of Medicine 3500 N Broad Street Philadelphia PA 19140 USA Anthony Harmar (1951-2014) formerly of the University of Edinburgh, Edinburgh, Scotland Nick Holliday Room CS6 The Medical School, Floor C Queen's Medical Centre Nottingham NG7 2UH UK Robert T. Jensen (BB3) National Institute of Diabetes & Kidney Diseases National Institutes of Health Building 10 Room 9C-103 NIH Bethesda MD 20892 USA Sadashiva Karnik (MAS1) Department of Molecular Cardiology Lerner Research Institute The Cleveland Clinic Foundation 9500 Euclid Ave. Cleveland, OH 44195 USA Evi Kostenis (GPR17) Section Molecular, Cellular and Pharmacobiology Institute for Pharmaceutical Biology University of Bonn Nussallee 6 53115 Bonn Germany Wen Chiy Liew (Past curator) Amy E. Monaghan (Past curator) Chido Mpamhanga (Past curator) Richard Neubig Michigan State University 1355 Bogue St B440 Life Sciences Building East Lansing MI 48824 Adam J Pawson (Past Senior Database Curator) Centre for Discovery Brain Sciences Edinburgh Medical School: Biomedical Sciences Room 338, Hugh Robson Building George Square Edinburgh, EH8 9XD Jean-Philippe Pin Institut de Génomique Fonctionnelle UMR 5203 CNRS – U 1191 INSERM – Univ. Montpellier 141 rue de la cardonille 34094 Montpellier Cedex 05 - France Joanna L. Sharman (Past senior developer) Centre for Discovery Brain Sciences Edinburgh Medical School: Biomedical Sciences Room 338 Hugh Robson Building George Square Edinburgh EH8 9XD UK Michael Spedding Spedding Research Solutions SARL 6 Rue Ampere Le Vesinet 78110 France Eliot Spindel (BB3) Oregon National Primate Research Center Division of Neuroscience 3181 SW Sam Jackson Park Road Portland OR 97239 USA Leigh Stoddart Division of Biochemistry and Molecular Biology Institute of Biomedical and Life Sciences University of Glasgow Glasgow G12 8QQ UK Laura Storjohann (GPR39) Salt Lake City UT 84124 Walter G. Thomas School of Biomedical Sciences The University of Queensland BNE, QUEENSLAND 4072 Australia Kalyan Tirupula (MAS1) Department of Molecular Cardiology Lerner Research Institute The Cleveland Clinic Foundation 9500 Euclid Ave. Cleveland, OH 44195 USA Patrick Vanderheyden Department of Molecular and Biochemical Pharmacology Vrije Universiteit Brussel Pleinlaan 2 1050, Brussels Belgium