Table 1.
Class A orphan GPCRs with putative endogenous ligands
| Nomenclature | HGNC, UniProt | Principal transduction | Endogenous agonists (pKi) | Radioligands (Kd) | Selective agonists (pKi) | Comment |
|---|---|---|---|---|---|---|
| GPR1 | GPR1, P46091 | – | chemerin (RARRES2, Q99969) (pKd 8.28) 2 | – | – | Reported to act as a co-receptor for HIV 86. |
| GPR3 | GPR3, P46089 | Gs | – | – | – | sphingosine 1-phosphate was reported to be an endogenous agonist 97, but this finding was not replicated in subsequent studies 106. Reported to activate adenylyl cyclase constitutively through Gs 21. Gene disruption results in premature ovarian aging 55, reduced β-amyloid deposition 96 and hypersensitivity to thermal pain 81 in mice. |
| GPR4 | GPR4, P46093 | Gs | – | – | – | An initial report suggesting activation by lysophosphatidylcholine and sphingosylphosphorylcholine 111 has been retracted 112. GPR4, GPR65, GPR68 and GPR132 are now thought to function as protein-sensing receptors detecting acidic pH [17],[85]. Gene disruption is associated with increased perinatal mortality and impaired vascular proliferation 113. |
| GPR6 | GPR6, P46095 | Gs | – | – | – | An initial report that sphingosine 1-phosphate (S1P) was a high-affinity ligand (EC50 value of 39nM) [36],[97] was not repeated by β-arrestin PathHunter[TM] assays [90],[106]. Reported to activate adenylyl cyclase constitutively through Gs and to be located intracellularly 75. Gpr6-deficient mice showed reduced striatal cyclic AMP production in vitro and selected alterations in instrumental conditioning in vitro. 62. |
| GPR12 | GPR12, P47775 | – | – | – | – | Reports that sphingosine 1-phosphate was a ligand of GPR12 [35],[97] have not been replicated in β-arrestin-based assays [90],[106]. Gene disruption results in dyslipidemia and obesity 6. |
| GPR15 | GPR15, P49685 | – | – | – | – | Reported to act as a co-receptor for HIV 19. In an infection-induced colitis model, Gpr15 knockout mice were more prone to tissue damage and inflammatory cytokine expression 47. |
| GPR17 | GPR17, Q13304 | – | LTC4 (pEC50 7.83 – 9.48) 16, LTD4 (pEC50 8.14 – 8.36) 16, UDP-glucose (pEC50 5.92 – 9.52) [5],[16], UDP-galactose (pEC50 5.96 – 8.92) [5],[16], UDP (pEC50 5.97 – 8.8) [5],[16] | – | – | Reported to be a dual leukotriene and UDP receptor 16. Another group instead proposed that GPR17 functions as a negative regulator of the CysLT1 receptor response to leukotriene D4 (LTD4). For further discussion, see 17. Reported to antagonize CysLT1 receptor signalling in vivo and in vitro 65. |
| GPR20 | GPR20, Q99678 | – | – | – | – | Reported to inhibit adenylyl cyclase constitutively through Gi/o 30. GPR20 deficient mice exhibit hyperactivity characterised by increased total distance travelled in an open field test 8. |
| GPR22 | GPR22, Q99680 | Gi/o | – | – | – | Gene disruption results in increased severity of functional decompensation following aortic banding 1. Identified as a susceptibility locus for osteoarthritis [23],[46],[98]. |
| GPR26 | GPR26, Q8NDV2 | Gs | – | – | – | Has been reported to activate adenylyl cyclase constitutively through Gs 40. Gpr26 knockout mice show increased levels of anxiety and depression-like behaviours 108. |
| GPR31 | GPR31, O00270 | – | 12S-HETE (Selective) (pEC50 9.55 - Mouse) 27 | – | – | – |
| GPR32 | GPR32, O75388 | Not yet established | resolvin D1 (Selective) (pEC50 11.06) 51, LXA4 (Selective) (pEC50 9.7) 51 | [3H]resolvin D1 (Agonist) (2x10-10 M) 51 | – | resolvin D1 (more potently than LxA4) has been demonstrated to activate GPR32 in two publications [15],[51]. The pairing was not replicated in a recent study based on β-arrestin recruitment 90. GPR32 is a pseudogene in mice and rats. |
| GPR34 | GPR34, Q9UPC5 | Gi/Go | lysophosphatidylserine (Selective) (pEC50 6.57 – 6.89) [48],[91] | – | – | Lysophosphatidylserine has been reported to be a ligand of GPR34 in several publications, but the pairing was not replicated in a recent study based on β-arrestin recruitment 90. Fails to respond to a variety of lipid-derived agents 106. Gene disruption results in an enhanced immune response 59. |
| GPR35 | GPR35, Q9HC97 | – | 2-oleoyl-LPA (pEC50 7.3 – 7.52) 73, kynurenic acid (pEC50 3.9 – 4.41) [90],[99] | – | – | Several studies have shown that kynurenic acid is an agonist of GPR35 but it remains controversial whether the proposed endogenous ligand reaches sufficient tissue concentrations to activate the receptor 53. 2-oleoyl-LPA has also been proposed as an endogenous ligand 73 but these results were not replicated in in a recent β-arrestin assay 90. The phosphodiesterase inhibitor zaprinast 95 has become widely used as a surrogate agonist to investigate GPR35 pharmacology and signaliing 95. GPR35 is also activated by the pharmaceutical adjunct pamoic acid 110. |
| GPR37 | GPR37, O15354 | Gi/Go | – | – | neuropeptide head activator (pEC50 7.96 – 8.48) 78 | Reported to associate and regulate the dopamine transporter 68 and to be a substrate for parkin 66. Gene disruption results in altered striatal signalling 67. |
| GPR39 | GPR39, O43194 | Gq/G11 | Zn2+ 33 | – | – | Zn2+ has been reported to be a potent and efficacious agonist of human, mouse and rat GPR39 105. obestatin (GHRL, Q9UBU3), a fragment from the ghrelin precursor, was reported initially as an endogenous ligand, but subsequent studies failed to reproduce these findings. Has been reported to be down-regulated in adipose tissue in obesity-related diabetes 10. Gene disruption results in obesity and altered adipocyte metabolism 77. |
| GPR50 | GPR50, Q13585 | – | – | – | – | GPR50 is structurally related to MT1 and MT2 melatonin receptors, with which it heterodimerises constitutively and specifically 57. GPR50 knockout mice display abnormal thermoregulation and are much more likely than wild-type mice to enter fasting-induced torpor 3. |
| GPR61 | GPR61, Q9BZJ8 | Gs | – | – | – | GPR61 deficient mice exhibit obesity associated with hyperphagia 70. Although no endogenous ligands have been identified, 5-(nonyloxy)tryptamine has been reported to be a low affinity inverse agonist 94. |
| GPR63 | GPR63, Q9BZJ6 | – | – | – | – | sphingosine 1-phosphate and dioleoylphosphatidic acid have been reported to be low affinity agonists for GPR63 72 but this finding was not replicated in a β-arrestin-based assay 106. |
| GPR65 | GPR65, Q8IYL9 | Gs | – | – | – | GPR4, GPR65, GPR68 and GPR132 are now thought to function as proton-sensing receptors detecting acidic pH [17],[85]. Reported to activate adenylyl cyclase; gene disruption leads to reduced eosinophlia in models of allergic airway disease 50. |
| GPR68 | GPR68, Q15743 | – | – | – | – | Gpr68 was previously identified as a receptor for sphingosylphosphorylcholine (SPC) 103, but the original publication has been retracted 104. GPR4, GPR65, GPR68 and GPR132 are now thought to function as protein-sensing receptors detecting acidic pH [17],[85]. A family of 3,5-disubstituted isoxazoles were identified as agonists of GPR68 82. |
| GPR75 | GPR75, O95800 | Gq/G11 | – | – | – | CCL5 (CCL5, P13501) was reported to be an agonist of GPR75 37, but the pairing could not be repeated in a recent β-arrestin assay 90. |
| GPR84 | GPR84, Q9NQS5 | Gi/Go | – | – | decanoic acid (pEC50 5.0 – 5.4) [90],[100], undecanoic acid (pEC50 5.1) 100, lauric acid (pEC50 5.05) 100 | Medium chain free fatty acids with carbon chain lengths of 9-14 activate GPR84 [92],[100]. A surrogate ligand for GPR84, 6-n-octylaminouracil has also been proposed 92. |
| GPR87 | GPR87, Q9BY21 | – | LPA (pEC50 7.44) [69],[93] | – | – | – |
| GPR88 | GPR88, Q9GZN0 | – | – | – | – | Gene disruption results in altered striatal signalling 63. |
| GPR132 | GPR132, Q9UNW8 | Gs | – | – | – | GPR4, GPR65, GPR68 and GPR132 are now thought to function as protein-sensing receptors detecting acidic pH [17],[85]. Reported to respond to lysophosphatidylcholine 41, but later retracted 102. |
| GPR149 | GPR149, Q86SP6 | – | – | – | – | Gpr149 knockout mice displayed increased fertility and enhanced ovulation, with increased levels of FSH receptor and cyclin D2 mRNA levels 20. |
| GPR183 | GPR183, P32249 | – | 7α,25-dihydroxycholesterol (Selective) (pEC50 8.1 – 9.85) [28],[60], 7α,27-dihydroxycholesterol (Selective) (pEC50 8.89) 60, 7β, 25-dihydroxycholesterol (Selective) (pEC50 8.68) 60, 7β, 27-dihydroxycholesterol (Selective) (pEC50 7.29) 60 | – | – | Two independent publications have shown that 7α,25-dihydroxycholesterol is an agonist of GPR183 and have demonstrated by mass spectrometry that this oxysterol is present endogenously in tissues [28],[60]. Gpr183-deficient mice show reduction in the early antibody response to a T-dependent antigen. GPR183-deficient B cells fail to migrate to the outer follicle and instead stay in the follicle centre [44],[76]. |
| LGR4 | LGR4, Q9BXB1 | – | R-spondin-2 (RSPO2, Q6UXX9) (Selective) (pEC50 12.52) 9, R-spondin-1 (RSPO1, Q2MKA7) (Selective) (pEC50 10.7) 9, R-spondin-3 (RSPO3, Q9BXY4) (Selective) (pEC50 10.7) 9, R-spondin-4 (RSPO4, Q2I0M5) (Selective) (pEC50 10.05) 9 | – | R-spondin-2 (RSPO2, Q6UXX9) (Selective) (pEC50 12.52) 9, R-spondin-1 (RSPO1, Q2MKA7) (Selective) (pEC50 10.7) 9, R-spondin-3 (RSPO3, Q9BXY4) (Selective) (pEC50 10.7) 9, R-spondin-4 (RSPO4, Q2I0M5) (Selective) (pEC50 10.05) 9 | LGR4 does not couple to heterotrimeric G proteins or to β-arrestin when stimulated by the R-spondins, indicating a unique mechanism of action. R-spondins bind to LGR4, which specifically associates with Frizzled and LRPs—proteins that are activated by the extracellular Wnt molecules and then trigger canonical Wnt signalling to increase gene expression [9],[18],[80]. Gene disruption leads to multiple developmental disorders [39],[64],[89],[101]. |
| LGR5 | LGR5, O75473 | – | R-spondin-2 (RSPO2, Q6UXX9) (Selective) (pEC50 12.0) 9, R-spondin-1 (RSPO1, Q2MKA7) (Selective) (pEC50 11.1) 9, R-spondin-3 (RSPO3, Q9BXY4) (Selective) (pEC50 11.0) 9, R-spondin-4 (RSPO4, Q2I0M5) (Selective) (pEC50 9.4) 9 | – | R-spondin-2 (RSPO2, Q6UXX9) (Selective) (pEC50 12.0) 9, R-spondin-1 (RSPO1, Q2MKA7) (Selective) (pEC50 11.1) 9, R-spondin-3 (RSPO3, Q9BXY4) (Selective) (pEC50 11.0) 9, R-spondin-4 (RSPO4, Q2I0M5) (Selective) (pEC50 9.4) 9 | The four R-spondins can bind to LGR4, LGR5, and LGR6, which specifically associate with Frizzled and LRPs—proteins that are activated by extracellular Wnt molecules- and then trigger canonical Wnt signalling to increase gene expression [9],[18]. |
| LGR6 | LGR6, Q9HBX8 | – | R-spondin-1 (RSPO1, Q2MKA7) (Selective) [9],[18], R-spondin-2 (RSPO2, Q6UXX9) (Selective) [9],[18], R-spondin-3 (RSPO3, Q9BXY4) (Selective) [9],[18], R-spondin-4 (RSPO4, Q2I0M5) (Selective) [9],[18] | – | – | – |
| MAS1 | MAS1, P04201 | Gq/G11 | angiotensin-(1-7) (AGT, P01019) (Selective) 84 | – | – | – |
| MRGPRD | MRGPRD, Q8TDS7 | Gi/Go | β-alanine (pEC50 4.8) [87],[90] | – | – | An endogenous peptide with a high degree of sequence similarity to angiotensin-(1-7) (AGT, P01019), alamandine, was shown to promote NO release in MrgD-transfected cells. The binding of alamandine to MRGPRD to was shown to be blocked by D-Pro7-angiotensin-(1–7), β-alanine and PD123319 54. Genetic ablation of MRGPRD+ neurons of adult mice decreased behavioural sensitivity to mechanical stimuli but not to thermal stimuli 11. |
| MRGPRX1 | MRGPRX1, Q96LB2 | Gq/G11 | BAM8-22 (PENK, P01210) (Selective) (pEC50 5.3 – 7.8) [13],[56],[90] | – | – | Reported to mediate the sensation of itch [61],[88]. Reports that BAM8-22 (PENK, P01210) was the most potent of a series of proenkephalin A–derived peptides as an agonist of MRGPRX1 in assays of calcium mobilisation and radioligand binding 56 were replicated in an independent study using a β-arrestin recruitment assay 90. |
| MRGPRX2 | MRGPRX2, Q96LB1 | – | PAMP-20 (ADM, P35318) (Selective) 42 | – | PAMP-12 (human) (pEC50 7.24 – 7.68) 42, CST-14 {Sp: Mouse, Rat} (pEC50 6.9 – 7.6) [42],[79],[90] | A diverse range of substances has been reported to be agonists of MRGPRX2, with cortistatin 14 the highest potency agonist in assays of calcium mobilisation 79, also confirmed in an independent study using a β-arrestin recruitment assay 90. |
| P2RY10 | P2RY10, O00398 | – | sphingosine 1-phosphate (Selective) (pEC50 7.3) 69, LPA (Selective) (pEC50 6.9) 69 | – | – | – |
| TAAR2 | TAAR2, Q9P1P5 | Gs | – | – | – | β-phenylethylamine > tryptamine 7 probable pseudogene in 10–15% of Asians due to a polymorphism (rs8192646) producing a premature stop codon at amino acid 168 17 see Page 139. |