Class A Orphans with no pharmacology | G protein-coupled receptors

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G protein-coupled receptors
Class A Orphans
Class A Orphans with no pharmacology

Class A Orphans with no pharmacology C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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This set contains Class A 'orphan' G protein-coupled receptors where the endogenous ligand(s) is not known, identified by NC-IUPHAR [11].

Receptors

Targets of relevance to immunopharmacology are highlighted in blue

GPR20 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	91
Nomenclature	GPR20
Previous and unofficial names	Gpcr5-1 \| P2Y4 \| G protein-coupled receptor 5-1
Genes	GPR20 (Hs), Gpr20 (Mm), Gpr20 (Rn)
Ensembl ID	ENSG00000204882 (Hs), ENSMUSG00000045281 (Mm), ENSRNOG00000007795 (Rn)
UniProtKB AC	Q99678 (Hs), Q8BYC4 (Mm), O35797 (Rn)
Principal transduction	G_i/G_o family
Comment	GPR20 deficient mice exhibit hyperactivity characterised by increased total distance travelled in an open field test [4].

GPR21 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	92
Nomenclature	GPR21
Genes	GPR21 (Hs), Gpr21 (Mm), Gpr21 (Rn)
Ensembl ID	ENSG00000188394 (Hs), ENSMUSG00000053164 (Mm), ENSRNOG00000042269 (Rn)
UniProtKB AC	Q99679 (Hs), Q8BX79 (Mm)
Principal transduction	G_q/G₁₁ family
Comment	Positive benefit in models of diabetes/obesity [12,26] were not observed in another study [32]. A cryo-EM structure of unliganded GPR21 bound to G proteins has been reported [21]. GRA2 is reported as an inverse agonist [3].

GPR22 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	93
Nomenclature	GPR22
Genes	GPR22 (Hs), Gpr22 (Mm), Gpr22 (Rn)
Ensembl ID	ENSG00000172209 (Hs), ENSMUSG00000044067 (Mm), ENSRNOG00000008423 (Rn)
UniProtKB AC	Q99680 (Hs), Q8BZL4 (Mm), D4A3U0 (Rn)
Principal transduction	G_i/G_o family
Comment	Gene disruption results in an increased susceptibility to cardiac decompensation following aortic banding [1].

GPR26 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	96
Nomenclature	GPR26
Genes	GPR26 (Hs), Gpr26 (Mm), Gpr26 (Rn)
Ensembl ID	ENSG00000154478 (Hs), ENSMUSG00000040125 (Mm), ENSRNOG00000047057 (Rn)
UniProtKB AC	Q8NDV2 (Hs), Q8BZA7 (Mm), Q9QXI3 (Rn)
Principal transduction	G_s family
Comment	Gpr26 knockout mice show increased levels of anxiety and depression-like behaviours [36], and elevated hyperphagia and adiposity [5].

GPR27 Show summary »« Hide summary More detailed page go icon to follow link

Target Id

Nomenclature

GPR27

Previous and unofficial names

SREB1 | super conserved receptor expressed in brain 1

Genes

GPR27 (Hs), Gpr27 (Mm), Gpr27 (Rn)

Ensembl ID

ENSG00000170837 (Hs), ENSMUSG00000072875 (Mm), ENSRNOG00000010880 (Rn)

UniProtKB AC

Q9NS67 (Hs), O54897 (Mm), Q9JJH3 (Rn)

Principal transduction

G_q/G₁₁ family

Agonists

compound 5128535 [28]

PT-91 [28]

compound 1a [PMID: 27184081] (Inverse agonist) [34]

Comment

A complex mix of plasmalogens evoked phosphorylation of ERK and PKB in mouse cultured hippocampal neurones that could be inhibited with shRNA directed against GPR27 [15]. Compound 5128535 [8-9,28] and PT-91 [28] function as surrogate agonists, while compound 1a is reported as an inverse agonist [34]. Knockdown of Gpr27 reduces endogenous mouse insulin promotor activity and glucose-stimulated insulin secretion [18].

GPR45 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	106
Nomenclature	GPR45
Previous and unofficial names	PSP24 \| high-affinity lysophosphatidic acid receptor \| PSP24alpha \| PSP24A
Genes	GPR45 (Hs), Gpr45 (Mm), Gpr45 (Rn)
Ensembl ID	ENSG00000135973 (Hs), ENSMUSG00000041907 (Mm), ENSRNOG00000016446 (Rn)
UniProtKB AC	Q9Y5Y3 (Hs), Q9EQQ4 (Mm)
Principal transduction	G_s family, G_i/G_o family
Comment	Increased adiposity at weaning and reduced hypothalamic expression of POMC [6]. Global disruption of Gpr45[17] or selectively in the paraventricular nucleus of the hypothalamus was associated with obesity [33].

GPR50 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	107
Nomenclature	GPR50
Previous and unofficial names	MTNRL \| H9 \| Mel1c \| melatonin-related receptor
Genes	GPR50 (Hs), Gpr50 (Mm), Gpr50 (Rn)
Ensembl ID	ENSG00000102195 (Hs), ENSMUSG00000056380 (Mm), ENSRNOG00000011335 (Rn)
UniProtKB AC	Q13585 (Hs), O88495 (Mm), Q62953 (Rn)
Principal transduction	G₁₂/G₁₃ family
Comment	GPR50 is structurally related to MT₁ and MT₂ melatonin receptors, with which it heterodimerises constitutively and specifically [20]. Gpr50 knockout mice display abnormal thermoregulation and are much more likely than wild-type mice to enter fasting-induced torpor [2].

GPR62 Show summary »« Hide summary More detailed page go icon to follow link

GPR78 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	116
Nomenclature	GPR78
Genes	GPR78 (Hs)
Ensembl ID	ENSG00000155269 (Hs)
UniProtKB AC	Q96P69 (Hs)
Principal transduction	G_s family
Comment	GPR78 has been reported to be constitutively active, coupled to elevated cAMP production [16].

GPR79 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	117
Nomenclature	GPR79
Previous and unofficial names	GPR79P \| G protein-coupled receptor 79, pseudogene
Genes	GPR79 (Hs)
Ensembl ID	ENSG00000232374 (Hs)
Principal transduction	-

GPR82 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	118
Nomenclature	GPR82
Genes	GPR82 (Hs), Gpr82 (Mm)
Ensembl ID	ENSG00000171657 (Hs), ENSMUSG00000047678 (Mm)
UniProtKB AC	Q96P67 (Hs), Q8BZR0 (Mm)
Principal transduction	-
Comment	Although lacking constitutive activity in recombinant expression [22], lysoPE and lysoPC are reported to act as inverse agonists [35].

GPR135 Show summary »« Hide summary More detailed page go icon to follow link

GPR141 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	131
Nomenclature	GPR141
Previous and unofficial names	axor115 \| G-protein coupled receptor PGR13
Genes	GPR141 (Hs), Gpr141 (Mm), Gpr141 (Rn)
Ensembl ID	ENSG00000187037 (Hs), ENSMUSG00000053101 (Mm), ENSRNOG00000059698 (Rn), ENSRNOG00000066332 (Rn)
UniProtKB AC	Q7Z602 (Hs), Q7TQP0 (Mm), Q7TQN5 (Rn)
Principal transduction	-
Comment	Disrupted expression elevated the immune response in leukocytes and experimental autoimmune encephalomyelitis [29].

GPR148 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	134
Nomenclature	GPR148
Previous and unofficial names	BTR \| PGR6 \| brain and testis restricted GPCR
Genes	GPR148 (Hs)
Ensembl ID	ENSG00000173302 (Hs)
UniProtKB AC	Q8TDV2 (Hs)
Principal transduction	-

GPR149 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	135
Nomenclature	GPR149
Previous and unofficial names	IEDA \| G-protein coupled receptor PGR10 \| induced early in differentiating astrocytes gene protein
Genes	GPR149 (Hs), Gpr149 (Mm), Gpr149 (Rn)
Ensembl ID	ENSG00000174948 (Hs), ENSMUSG00000043441 (Mm), ENSRNOG00000014793 (Rn)
UniProtKB AC	Q86SP6 (Hs), Q3UVY1 (Mm), Q924Y8 (Rn)
Principal transduction	-
Comment	Gpr149 knockout mice displayed increased fertility and enhanced ovulation, with increased levels of FSH receptor and cyclin D2 mRNA levels [10].

GPR150 Show summary »« Hide summary More detailed page go icon to follow link

GPR152 Show summary »« Hide summary More detailed page go icon to follow link

GPR153 Show summary »« Hide summary More detailed page go icon to follow link

GPR161 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	141
Nomenclature	GPR161
Previous and unofficial names	G-protein coupled receptor RE2
Genes	GPR161 (Hs), Gpr161 (Mm), Gpr161 (Rn)
Ensembl ID	ENSG00000143147 (Hs), ENSMUSG00000040836 (Mm), ENSRNOG00000003073 (Rn)
UniProtKB AC	Q8N6U8 (Hs), B2RPY5 (Mm), F1M5Q2 (Rn)
Principal transduction	-
Comment	Appears to function as a negative regulator of Sonic hedgehog signalling [23-24,27,30]. A cryo-EM structure suggests the second extracellular loop may auto-activate the receptor [14].

GPR176 Show summary »« Hide summary More detailed page go icon to follow link

MRGPRE Show summary »« Hide summary More detailed page go icon to follow link

Target Id	153
Nomenclature	MRGPRE
Previous and unofficial names	GPR167 \| MRGE \| MAS-related gene E \| MAS-related GPR
Genes	MRGPRE (Hs), Mrgpre (Mm), Mrgpre (Rn)
Ensembl ID	ENSG00000184350 (Hs), ENSMUSG00000048965 (Mm), ENSRNOG00000065330 (Rn)
UniProtKB AC	Q86SM8 (Hs), Q91ZB7 (Mm), Q7TN40 (Rn)
Principal transduction	-
Comment	May function to inhibit arachidonic acid release in the presence of Ang-1-7 [13]. See reviews [7] and [31].

MRGPRG Show summary »« Hide summary More detailed page go icon to follow link

MRGPRX3 Show summary »« Hide summary More detailed page go icon to follow link

Target Id	158
Nomenclature	MRGPRX3
Previous and unofficial names	MrgA \| Mrgpra \| Mrga10 \| SNSR1 [19] \| Sensory neuron-specific G protein-coupled receptor 1
Genes	MRGPRX3 (Hs)
Ensembl ID	ENSG00000179826 (Hs)
UniProtKB AC	Q96LB0 (Hs)
Principal transduction	G_q/G₁₁ family
Comment	Mrgprx3 is a pseudogene in mice.

References

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1. Adams JW, Wang J, Davis JR, Liaw C, Gaidarov I, Gatlin J, Dalton ND, Gu Y, Ross J, Behan D, Chien K, Connolly D. (2008) Myocardial expression, signaling, and function of GPR22: a protective role for an orphan G protein-coupled receptor. Am J Physiol Heart Circ Physiol, 295 (2): H509-21. [PMID:18539757]

2. Bechtold DA, Sidibe A, Saer BR, Li J, Hand LE, Ivanova EA, Darras VM, Dam J, Jockers R, Luckman SM et al.. (2012) A role for the melatonin-related receptor GPR50 in leptin signaling, adaptive thermogenesis, and torpor. Curr Biol, 22 (1): 70-7. [PMID:22197240]

3. Bordano V, Kinsella GK, Cannito S, Dianzani C, Gigliotti CL, Stephens JC, Monge C, Bocca C, Rosa AC, Miglio G et al.. (2022) G protein-coupled receptor 21 in macrophages: An in vitro study. Eur J Pharmacol, 926: 175018. [PMID:35537492]

4. Brennan, Thomas et al.. (2007) Transgenic mice containing GPCR5-1 gene disruptions. Patent number: US2007/0074299. Assignee: Deltagen. Priority date: 28/08/1999. Publication date: 29/03/2007.

5. Chen D, Liu X, Zhang W, Shi Y. (2012) Targeted inactivation of GPR26 leads to hyperphagia and adiposity by activating AMPK in the hypothalamus. PLoS One, 7 (7): e40764. [PMID:22815809]

6. Cui J, Ding Y, Chen S, Zhu X, Wu Y, Zhang M, Zhao Y, Li TR, Sun LV, Zhao S et al.. (2016) Disruption of Gpr45 causes reduced hypothalamic POMC expression and obesity. J Clin Invest, 126 (9): 3192-206. [PMID:27500489]

7. Davenport AP, Alexander SP, Sharman JL, Pawson AJ, Benson HE, Monaghan AE, Liew WC, Mpamhanga CP, Bonner TI, Neubig RR et al.. (2013) International Union of Basic and Clinical Pharmacology. LXXXVIII. G protein-coupled receptor list: recommendations for new pairings with cognate ligands. Pharmacol Rev, 65 (3): 967-86. [PMID:23686350]

8. Dolanc D, Zorec TM, Smole Z, Maver A, Horvat A, Pillaiyar T, Trkov Bobnar S, Vardjan N, Kreft M, Chowdhury HH et al.. (2022) The Activation of GPR27 Increases Cytosolic L-Lactate in 3T3 Embryonic Cells and Astrocytes. Cells, 11 (6). [PMID:35326460]

9. Dupuis N, Laschet C, Franssen D, Szpakowska M, Gilissen J, Geubelle P, Soni A, Parent AS, Pirotte B, Chevigné A et al.. (2017) Activation of the Orphan G Protein-Coupled Receptor GPR27 by Surrogate Ligands Promotes β-Arrestin 2 Recruitment. Mol Pharmacol, 91 (6): 595-608. [PMID:28314853]

10. Edson MA, Lin YN, Matzuk MM. (2010) Deletion of the novel oocyte-enriched gene, Gpr149, leads to increased fertility in mice. Endocrinology, 151 (1): 358-68. [PMID:19887567]

11. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]

12. Gardner J, Wu S, Ling L, Danao J, Li Y, Yeh WC, Tian H, Baribault H. (2012) G-protein-coupled receptor GPR21 knockout mice display improved glucose tolerance and increased insulin response. Biochem Biophys Res Commun, 418 (1): 1-5. [PMID:22155242]

13. Gembardt F, Grajewski S, Vahl M, Schultheiss HP, Walther T. (2008) Angiotensin metabolites can stimulate receptors of the Mas-related genes family. Mol Cell Biochem, 319 (1-2): 115-23. [PMID:18636314]

14. Hoppe N, Harrison S, Hwang SH, Chen Z, Karelina M, Deshpande I, Suomivuori CM, Palicharla VR, Berry SP, Tschaikner P et al.. (2024) GPR161 structure uncovers the redundant role of sterol-regulated ciliary cAMP signaling in the Hedgehog pathway. Nat Struct Mol Biol, 31 (4): 667-677. [PMID:38326651]

15. Hossain MS, Mineno K, Katafuchi T. (2016) Neuronal Orphan G-Protein Coupled Receptor Proteins Mediate Plasmalogens-Induced Activation of ERK and Akt Signaling. PLoS One, 11 (3): e0150846. [PMID:26934370]

16. Jones PG, Nawoschik SP, Sreekumar K, Uveges AJ, Tseng E, Zhang L, Johnson J, He L, Paulsen JE, Bates B, Pausch MH. (2007) Tissue distribution and functional analyses of the constitutively active orphan G protein coupled receptors, GPR26 and GPR78. Biochim Biophys Acta, 1770 (6): 890-901. [PMID:17363172]

17. Karolczak EO, Li C, Alcantara IC, Cohen IM, Gao C, Xiao C, Goldschmidt AI, Pinkus CA, Li J, Li MM et al.. (2025) Uncovering the role of Gpr45 in obesity regulation. Mol Metab, 98: 102174. [PMID:40449730]

18. Ku GM, Pappalardo Z, Luo CC, German MS, McManus MT. (2012) An siRNA screen in pancreatic beta cells reveals a role for Gpr27 in insulin production. PLoS Genet, 8 (1): e1002449. [PMID:22253604]

19. Lembo PM, Grazzini E, Groblewski T, O'Donnell D, Roy MO, Zhang J, Hoffert C, Cao J, Schmidt R, Pelletier M et al.. (2002) Proenkephalin A gene products activate a new family of sensory neuron--specific GPCRs. Nat Neurosci, 5 (3): 201-9. [PMID:11850634]

20. Levoye A, Dam J, Ayoub MA, Guillaume JL, Couturier C, Delagrange P, Jockers R. (2006) The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization. EMBO J, 25 (13): 3012-23. [PMID:16778767]

21. Lin X, Chen B, Wu Y, Han Y, Qi A, Wang J, Yang Z, Wei X, Zhao T, Wu L et al.. (2023) Cryo-EM structures of orphan GPR21 signaling complexes. Nat Commun, 14 (1): 216. [PMID:36639690]

22. Martin AL, Steurer MA, Aronstam RS. (2015) Constitutive Activity among Orphan Class-A G Protein Coupled Receptors. PLoS One, 10 (9): e0138463. [PMID:26384023]

23. Mukhopadhyay S, Wen X, Ratti N, Loktev A, Rangell L, Scales SJ, Jackson PK. (2013) The ciliary G-protein-coupled receptor Gpr161 negatively regulates the Sonic hedgehog pathway via cAMP signaling. Cell, 152 (1-2): 210-23. [PMID:23332756]

24. Nozaki S, Katoh Y, Terada M, Michisaka S, Funabashi T, Takahashi S, Kontani K, Nakayama K. (2017) Regulation of ciliary retrograde protein trafficking by the Joubert syndrome proteins ARL13B and INPP5E. J Cell Sci, 130 (3): 563-576. [PMID:27927754]

25. Oishi A, Karamitri A, Gerbier R, Lahuna O, Ahmad R, Jockers R. (2017) Orphan GPR61, GPR62 and GPR135 receptors and the melatonin MT₂ receptor reciprocally modulate their signaling functions. Sci Rep, 7 (1): 8990. [PMID:28827538]

26. 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]

27. Pal K, Hwang SH, Somatilaka B, Badgandi H, Jackson PK, DeFea K, Mukhopadhyay S. (2016) Smoothened determines β-arrestin-mediated removal of the G protein-coupled receptor Gpr161 from the primary cilium. J Cell Biol, 212 (7): 861-75. [PMID:27002170]

28. Pillaiyar T, Wozniak M, Abboud D, Rasch A, Liebing AD, Poso A, Kronenberger T, Stäubert C, Laufer SA, Hanson J. (2023) Development of Ligands for the Super Conserved Orphan G Protein-Coupled Receptor GPR27 with Improved Efficacy and Potency. J Med Chem, 66 (24): 17118-17137. [PMID:38060818]

29. Sawabe A, Okazaki S, Nakamura A, Goitsuka R, Kaifu T. (2024) The orphan G protein-coupled receptor 141 expressed in myeloid cells functions as an inflammation suppressor. J Leukoc Biol, 115 (5): 935-945. [PMID:38226682]

30. Shimada IS, Hwang SH, Somatilaka BN, Wang X, Skowron P, Kim J, Kim M, Shelton JM, Rajaram V, Xuan Z et al.. (2018) Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis. Cell Rep, 22 (5): 1169-1184. [PMID:29386106]

31. 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]

32. Wang J, Pan Z, Baribault H, Chui D, Gundel C, Véniant M. (2016) GPR21 KO mice demonstrate no resistance to high fat diet induced obesity or improved glucose tolerance. F1000Res, 5: 136. [PMID:27081476]

33. Xun Y, Jiang Y, Xu B, Tang M, Ludwig S, Nakamura K, Mukhopadhyay S, Liu C, Beutler B, Zhang Z. (2025) GPR45 modulates Gα_s at primary cilia of the paraventricular hypothalamus to control food intake. Science, 388 (6751): eadp3989. [PMID:40472089]

34. Yanai T, Kurosawa A, Nikaido Y, Nakajima N, Saito T, Osada H, Konno A, Hirai H, Takeda S. (2016) Identification and molecular docking studies for novel inverse agonists of SREB, super conserved receptor expressed in brain. Genes Cells, 21 (7): 717-27. [PMID:27184081]

35. Yasuda D, Hamano F, Masuda K, Dahlström M, Kobayashi D, Sato N, Hamakubo T, Shimizu T, Ishii S. (2023) Inverse agonism of lysophospholipids with cationic head groups at Gi-coupled receptor GPR82. Eur J Pharmacol, 954: 175893. [PMID:37392830]

36. 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]

Citation information

Database page citation:

Class A Orphans with no pharmacology. Accessed on 12/09/2025. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=1111.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.