GPR15

Target id: 87

Nomenclature: GPR15

Family: Class A Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

This receptor has a proposed ligand; see the Latest Pairings page for more information.

   GtoImmuPdb view: OFF :     GPR15 has curated GtoImmuPdb data

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 360 3q11.2-q13.1 GPR15 G protein-coupled receptor 15 19
Mouse 7 360 16 C1.2 Gpr15 G protein-coupled receptor 15
Rat 7 377 11q12 Gpr15 G protein-coupled receptor 15
Previous and Unofficial Names
BOB | Brother of Bonzo
Database Links
Specialist databases
GPCRDB gpr15_human (Hs), gpr15_mouse (Mm)
Other databases
Ensembl Gene
Entrez Gene
GenitoUrinary Development Molecular Anatomy Project
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Immunopharmacology Comments
Several lines of evidence suggest that GPR15 is a chemoattractant receptor supporting the trafficking of T effector cells to the colon [18,33]. In humans GPR15 is expressed by effector cells, including pathogenic TH2 cells in ulcerative colitis [16,33]. GPR15 also acts as a viral co-receptor for human immunodeficiency virus type 1 and 2 [35,48].
Immuno Cell Type Associations
Immuno Cell Type:  T cells
Cell Ontology Term:   T-helper 2 cell (CL:0000546)
Comment: 
References:  33
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process ID:  2
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  T cell migration (GO:0072678) IEA
References: 
Immuno Process:  Chemotaxis & migration
Immuno Process ID:  10
Comment: 
GO Annotation:  Associated to GO processes, IEA only
GO Processes:  T cell migration (GO:0072678) IEA
References: 
Tissue Distribution
Alveolar Macrophages, CD4+ T lymphocytes
Species:  Human
Technique:  RT-PCR
References:  15
Colon (high); spleen, peripheral blood leukocytes (medium); thymus and small intestine (weak)
Species:  Human
Technique:  Northern blot hybridisation
References:  11
Small bowel and colonic mucosa, lymph node, prostate, testis, and liver
Species:  Human
Technique:  Western blot
References:  8
Intestinal epithelium, lamina propria, mononuclear cells and crypt cells
Species:  Human
Technique:  RNA in situ hybridisation and indirect immunofluorescent staining
References:  8
Peripheral blood mononuclear cells
Species:  Rhesus macaque
Technique:  RT-PCR
References:  13
Basal surfaces of gut epithelia, apical surfaces, mononuclear cells in laminar propria of small and large bowel
Species:  Rhesus macaque
Technique:  Immunocytochemistry
References:  27
Tissue Distribution Comments
RT-PCR detected GPR15 in phytohaemagglutinin-stimulated peripheral blood mononuclear cells (PBMC), purified T cells, with weak detection in unstimulated PBMC [11].

The detection of GPR15 in the colon suggests it may be important for transmission of HIV and SIV, and the authors speculate that the high expression in the colon suggests it may be present in non-lymphoid cells [11].

Brain capillary endothelial cells, the targets of CD4 independent infection by HIV-1 and SIV strains, were found not to express GPR15 [13]. RT-PCR analysis of CEMX174, Hut-78, C8166, monocytes, monocyte-derived macrophages, and peripheral blood leukocyte cell lines detected GPR15 expression [12]. Not detected in primitive blood cells by RT-PCR analysis [43].

Human fetal and simian adult astrocytes were shown to express GPR15 when analysed using RT-PCR, and this expression increased following treatment with TNFα and IL-1β [10].

For expression levels on immune cells of primate species see [14].

Analysis of the expression of GPR15 in the rhesus macaque gut showed that gut epithelial cell apoptosis coincided with interactions between SIV virus and GPR15-expressing cells [27].
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Physiological Consequences of Altering Gene Expression
Knockout mice display a tendency to intestinal inflammation. In an infection-induced colitis model, knockout mice were more prone to tissue damage and inflammatory cytokine expression.
Species:  Mouse
Tissue:  Large intestine
Technique:  Gene knockout
References:  23
Gene Expression and Pathophysiology Comments
GPR15 mediates the gp120-induced calcium signalling and microtubule loss in HIV-infected cells. The authors speculate that activation of GPR15 induced by gpr120 is a probable cause of HIV enteropathy [8]. It has been shown that the effects of gpr120-mediated enteropathy of the intestine, including microtubule depolymerisation, can be inhibited by antibodies against GPR15 through disruption of signal transduction [29].
Biologically Significant Variants
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  P37S
Global MAF (%):  20
Subpopulation MAF (%):  AFR|AMR|ASN|EUR: 6|28|35|14
Minor allele count:  T=0.200/436
SNP accession: 
Validation:  1000 Genomes, HapMap
Type:  Single nucleotide polymorphism
Species:  Human
Amino acid change:  M112V
Global MAF (%):  2
Subpopulation MAF (%):  AFR: 7
Minor allele count:  G=0.015/33
Comment on frequency:  Low frequency (<10% in all tested populations)
SNP accession: 
Validation:  1000 Genomes, Frequency, Multiple observations
Type:  Naturally occurring SNP
Species:  Human
Amino acid change:  V252F
Comment on frequency:  Low frequency (low frequency means <10% in all tested populations)
SNP accession: 
Type:  Naturally occurring SNP
Species:  Human
Amino acid change:  M112V
Comment on frequency:  Low frequency (low frequency means <10% in all tested populations)
SNP accession: 
Biologically Significant Variant Comments
There was no correlation observed between polymorphisms in the GPR15 gene in humans with plasma viral concentration [52].
General Comments
The mouse orthologue of gpr15 can be induced by dioxin [42].

It has been reported in several studies that GPR15 acts as a co-receptor for HIV, and is used by HIV-2 strains [9,13,17,21,32,47]. There is some disagreement in the literature as to whether GPR15 is also used as a coreceptor by HIV-1 strains, with some studies finding it is not [55], while others showing it is used by some strains but the significance of its use in relation to other coreceptors is unclear [4]. R5X4 HIV-1 strains have been shown to use GPR15 as a coreceptor [6-7]. Chan et al. discuss the difficulty in studying the role of GPR15 as a coreceptor. Later studies showed that some HIV-1 strains do use GPR15 as a coreceptor and replicate within GPR15-expressing cells, albeit with lower efficiency than other receptors [34,39]. Use of GPR15 as a coreceptor depends on the genetic subtype and biological phenotype of the strain, and in its role as a cofactor GPR15 may be important in influencing the pathogenesis and transmission of HIV [39].

GPR15 is also a co-receptor for primary SIV strains [11,15,55]. This has been demonstrated using GHOST and U87 cell line assays [37]. It has also been shown that the use of GPR15 for cell entry by SIV strains is comparable in its efficiency with use of CCR5, and that SIVmac strains of the virus from rhesus macaques can use both the human and simian receptors [40]. However a later study showed that GPR15 was used with less efficiency than CCR5 by SIV strains and is rarely used by HIV-1 strains [49]. A high degree of sequence similarity has been shown between the human and Rhesus macaque receptors [30]. Edinger et al. showed that GPR15 is used in the entry mechanism of a number of SIV strains but use of the receptor did not correlate with either SIV or HIV tropism [12]. SIV strains SIVmac251 and SIVmac239 has been shown to utilise GPR15 as a coreceptor [26,55], and other SIVmac strains show preferential use of GPR15 over other coreceptors [41,47]. A macrophage-tropic SIVMne clone was shown to use GPR15 as a coreceptor [24]. Envelope proteins from HIV and SIV strains have been found to utilise GPR15 to enable their entry into cells [20,46], and that cell entry via fusion with GPR15 is CD4-dependent [1,12-13]. However, a more recent study has shown GPR15 to have a role in CD4-independent cell entry [44]. Eight HIV-1 envelope glycoproteins can use GPR15 to enable cell entry [34]. SIV/17E-Fr, SIV/B670-Cl 3, and SIVsmE543 envelope proteins may mediate fusion with cells expressing CD4 and GPR15 [13]. It is speculated that variation in the expression pattern of GPR15 may be a contributing factor in determining the outcome of SIV infection [12]. Xiao et al. shows the correlation between the adaptation of viral strains to use co-receptors and infectivity/disease progression, implying that as a coreceptor there may be future interest in GPR15 as a therapeutic target [53].

Entry via GPR15 of a SIVmac239 clone is shown to be dependent on a single amino acid residue in the V3 loop of the clone [41]. However, this study also states that the role of GPR15 in the pathogenesis and replication of HIV-2 and SIV strains is unclear. Inhibition of the SIV envelope protein-mediated fusion with GPR15-expressing cells are explored by [54] and by the use of amino acid substitutions in the SIV Env protein by Meister et al [2]. Their results show that GPR15-utilisation can be impaired by a L320K-P321R substitution in the N-terminal half of the SIVmac V3 loop. Other substitutions in the V3 loop of SIV envelope protein have been shown to disrupt use of GPR15 as a coreceptor [21,38]. The importance of the V3 loop is confirmed by [21].

There is a high degree of sequence similarity between human and monkey receptors GPR15 receptors [11] and a high degree of sequence similarity between the amino-terminal regions of GPR15 and CCR5. HIV-1 virus strains ADA and YU2 show weak use of GPR15 as a coreceptor [15].

The original cloning study for GPR15 showed sequence similarity with angiotensin receptors AT1 and AT2, the interleukin 8b receptor and the orphan receptors GPR1 and AGTL1 [19]. The high degree of sequence similarity with GPR1 is consistent with the finding that almost all viral strains using GPR15 as a coreceptor also use GPR1 [12]. GPR15 was later shown to have high sequence similarity to GPR25 [22].

Changes in DNA methylation of the GPR15 gene locus have been linked to cigarette smoking, in an analysis of DNA from peripheral blood leukocytes using Illumina Human methylation 27K Beadchip; these results were validated by pyrosequencing [51]. The results from this study showed hypomethylation of the cg19859270 locus for current smokers and hypermethylation in former smokers when compared to controls.

It has been demonstrated that morphine does not affect gene expression of GPR15 [31].

African green monkey strains of SIV have been shown to use GPR15 as a coreceptor but with lower efficiency than CXCR4 [25].

Use of coreceptors by both HIV and SIV strains can evolve over the course of an infection with SIVsm strains showing a decrease in GPR15 use over time [50]. Study of the use of GPR15 as a coreceptor by HIV-2 strains shows that it is one of three coreceptors used mainly by low-pathogenic strains but was also shown to be one of the main coreceptors used in individuals with viremia, indicating there is no correlation between disease progression and coreceptor use [3]. HIV-2 isolates able to fuse with GPR15 in the absence of CD4 include VCP and ROD/B [28].

Cell surface expression of GPR15 is significantly increased following activation of phosphoinositide 3-kinase [5], and is mediated by mode III binding of 14-3-3 proteins to the receptor's C terminus [36].

Xenotropic Murine leukemia Virus-related virus (XMRV) replication has been observed in cells expressing GPR15 [45].

References

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1. Albright AV, Shieh JT, Itoh T, Lee B, Pleasure D, O'Connor MJ, Doms RW, González-Scarano F. (1999) Microglia express CCR5, CXCR4, and CCR3, but of these, CCR5 is the principal coreceptor for human immunodeficiency virus type 1 dementia isolates. J Virol73: 205-213. [PMID:9847323]

2. Barrowcliffe TW, Gutteridge JM, Dormandy TL. (1975) The effect of fatty-acid autoxidation products on blood coagulation. Thromb Diath Haemorrh33 (2): 271-7. [PMID:1138422]

3. Blaak H, Boers PH, Gruters RA, Schuitemaker H, van der Ende ME, Osterhaus AD. (2005) CCR5, GPR15, and CXCR6 are major coreceptors of human immunodeficiency virus type 2 variants isolated from individuals with and without plasma viremia. J. Virol.79 (3): 1686-700. [PMID:15650194]

4. Chan SY, Speck RF, Power C, Gaffen SL, Chesebro B, Goldsmith MA. (1999) V3 recombinants indicate a central role for CCR5 as a coreceptor in tissue infection by human immunodeficiency virus type 1. J. Virol.73 (3): 2350-8. [PMID:9971818]

5. Chung JJ, Okamoto Y, Coblitz B, Li M, Qiu Y, Shikano S. (2009) PI3K/Akt signalling-mediated protein surface expression sensed by 14-3-3 interacting motif. FEBS J.276 (19): 5547-58. [PMID:19691494]

6. Cilliers T, Nhlapo J, Coetzer M, Orlovic D, Ketas T, Olson WC, Moore JP, Trkola A, Morris L. (2003) The CCR5 and CXCR4 coreceptors are both used by human immunodeficiency virus type 1 primary isolates from subtype C. J. Virol.77 (7): 4449-56. [PMID:12634405]

7. Cilliers T, Willey S, Sullivan WM, Patience T, Pugach P, Coetzer M, Papathanasopoulos M, Moore JP, Trkola A, Clapham P et al.. (2005) Use of alternate coreceptors on primary cells by two HIV-1 isolates. Virology339 (1): 136-44. [PMID:15992849]

8. Clayton F, Kotler DP, Kuwada SK, Morgan T, Stepan C, Kuang J, Le J, Fantini J. (2001) Gp120-induced Bob/GPR15 activation: a possible cause of human immunodeficiency virus enteropathy. Am. J. Pathol.159 (5): 1933-9. [PMID:11696454]

9. Coetzer M, Nedellec R, Cilliers T, Meyers T, Morris L, Mosier DE. (2010) Extreme Genetic Divergence Is Required for Coreceptor Switching in HIV-1 Subtype C. J Acquir Immune Defic Syndr,  [Epub ahead of print]. [PMID:20921899]

10. Croitoru-Lamoury J, Guillemin GJ, Boussin FD, Mognetti B, Gigout LI, Chéret A, Vaslin B, Le Grand R, Brew BJ, Dormont D. (2003) Expression of chemokines and their receptors in human and simian astrocytes: evidence for a central role of TNF alpha and IFN gamma in CXCR4 and CCR5 modulation. Glia41 (4): 354-70. [PMID:12555203]

11. Deng H, Unutmaz D, KewalRamani VN, Littman DR. (1997) Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature388: 296-300. [PMID:9230441]

12. Edinger AL, Hoffman TL, Sharron M, Lee B, O'Dowd B, Doms RW. (1998) Use of GPR1, GPR15, and STRL33 as coreceptors by diverse human immunodeficiency virus type 1 and simian immunodeficiency virus envelope proteins. Virology249 (2): 367-78. [PMID:9791028]

13. Edinger AL, Mankowski JL, Doranz BJ, Margulies BJ, Lee B, Rucker J, Sharron M, Hoffman TL, Berson JF, Zink MC, Hirsch VM, Clements JE, Doms RW. (1997) CD4-independent, CCR5-dependent infection of brain capillary endothelial cells by a neurovirulent simian immunodeficiency virus strain. Proc. Natl. Acad. Sci. U.S.A.94 (26): 14742-7. [PMID:9405683]

14. Elbim C, Monceaux V, Mueller YM, Lewis MG, François S, Diop O, Akarid K, Hurtrel B, Gougerot-Pocidalo MA, Lévy Y et al.. (2008) Early divergence in neutrophil apoptosis between pathogenic and nonpathogenic simian immunodeficiency virus infections of nonhuman primates. J. Immunol.181 (12): 8613-23. [PMID:19050281]

15. Farzan M, Choe H, Martin K, Marcon L, Hofmann W, Karlsson G, Sun Y, Barrett P, Marchand N, Sullivan N, Gerard N, Gerard C, Sodroski J. (1997) Two orphan seven-transmembrane segment receptors which are expressed in CD4-positive cells support simian immunodeficiency virus infection. J. Exp. Med.186 (3): 405-11. [PMID:9236192]

16. Fischer A, Zundler S, Atreya R, Rath T, Voskens C, Hirschmann S, López-Posadas R, Watson A, Becker C, Schuler G et al.. (2016) Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut65 (10): 1642-64. [PMID:26209553]

17. Gharu L, Ringe R, Bhattacharya J. (2012) Evidence of extended alternate coreceptor usage by HIV-1 clade C envelope obtained from an Indian patient. Virus Res.163 (1): 410-4. [PMID:22086059]

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19. Heiber M, Marchese A, Nguyen T, Heng HH, George SR, O'Dowd BF. (1996) A novel human gene encoding a G-protein-coupled receptor (GPR15) is located on chromosome 3. Genomics32 (3): 462-5. [PMID:8838812]

20. Isaacman-Beck J, Hermann EA, Yi Y, Ratcliffe SJ, Mulenga J, Allen S, Hunter E, Derdeyn CA, Collman RG. (2009) Heterosexual transmission of human immunodeficiency virus type 1 subtype C: Macrophage tropism, alternative coreceptor use, and the molecular anatomy of CCR5 utilization. J. Virol.83 (16): 8208-20. [PMID:19515785]

21. Jiang C, Parrish NF, Wilen CB, Li H, Chen Y, Pavlicek JW, Berg A, Lu X, Song H, Tilton JC et al.. (2011) Primary infection by a human immunodeficiency virus with atypical coreceptor tropism. J. Virol.85 (20): 10669-81. [PMID:21835785]

22. Jung BP, Nguyen T, Kolakowski LF, Lynch KR, Heng HH, George SR, O'Dowd BF. (1997) Discovery of a novel human G protein-coupled receptor gene (GPR25) located on chromosome 1. Biochem. Biophys. Res. Commun.230 (1): 69-72. [PMID:9020062]

23. Kim SV, Xiang WV, Kwak C, Yang Y, Lin XW, Ota M, Sarpel U, Rifkin DB, Xu R, Littman DR. (2013) GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science340 (6139): 1456-9. [PMID:23661644]

24. Kimata JT, Gosink JJ, KewalRamani VN, Rudensey LM, Littman DR, Overbaugh J. (1999) Coreceptor specificity of temporal variants of simian immunodeficiency virus Mne. J. Virol.73 (2): 1655-60. [PMID:9882375]

25. Kuhmann SE, Madani N, Diop OM, Platt EJ, Morvan J, Müller-Trutwin MC, Barré-Sinoussi F, Kabat D. (2001) Frequent substitution polymorphisms in African green monkey CCR5 cluster at critical sites for infections by simian immunodeficiency virus SIVagm, implying ancient virus-host coevolution. J. Virol.75 (18): 8449-60. [PMID:11507190]

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29. Maresca M, Mahfoud R, Garmy N, Kotler DP, Fantini J, Clayton F. (2003) The virotoxin model of HIV-1 enteropathy: involvement of GPR15/Bob and galactosylceramide in the cytopathic effects induced by HIV-1 gp120 in the HT-29-D4 intestinal cell line. J. Biomed. Sci.10 (1): 156-66. [PMID:12566994]

30. Margulies BJ, Hauer DA, Clements JE. (2001) Identification and comparison of eleven rhesus macaque chemokine receptors. AIDS Res. Hum. Retroviruses17 (10): 981-6. [PMID:11461684]

31. Miyagi T, Chuang LF, Doi RH, Carlos MP, Torres JV, Chuang RY. (2000) Morphine induces gene expression of CCR5 in human CEMx174 lymphocytes. J. Biol. Chem.275 (40): 31305-10. [PMID:10887175]

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33. Nguyen LP, Pan J, Dinh TT, Hadeiba H, O'Hara 3rd E, Ebtikar A, Hertweck A, Gökmen MR, Lord GM, Jenner RG et al.. (2015) Role and species-specific expression of colon T cell homing receptor GPR15 in colitis. Nat. Immunol.16 (2): 207-13. [PMID:25531831]

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35. Okamoto Y, Bernstein JD, Shikano S. (2013) Role of C-terminal membrane-proximal basic residues in cell surface trafficking of HIV coreceptor GPR15 protein. J. Biol. Chem.288 (13): 9189-99. [PMID:23430259]

36. Okamoto Y, Shikano S. (2011) Phosphorylation-dependent C-terminal binding of 14-3-3 proteins promotes cell surface expression of HIV co-receptor GPR15. J. Biol. Chem.286 (9): 7171-81. [PMID:21189250]

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45. Setty MK, Devadas K, Ragupathy V, Ravichandran V, Tang S, Wood O, Gaddam DS, Lee S, Hewlett IK. (2011) XMRV: usage of receptors and potential co-receptors. Virol. J.8: 423. [PMID:21896167]

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47. Unutmaz D, KewalRamani VN, Littman DR. (1998) G protein-coupled receptors in HIV and SIV entry: new perspectives on lentivirus-host interactions and on the utility of animal models. Semin. Immunol.10 (3): 225-36. [PMID:9653049]

48. Vödrös D, Fenyö EM. (2005) Quantitative evaluation of HIV and SIV co-receptor use with GHOST(3) cell assay. Methods Mol. Biol.304: 333-42. [PMID:16061987]

49. Vödrös D, Thorstensson R, Biberfeld G, Schols D, De Clercq E, Fenyö EM. (2001) Coreceptor usage of sequential isolates from cynomolgus monkeys experimentally Infected with simian immunodeficiency virus (SIVsm). Virology291 (1): 12-21. [PMID:11878872]

50. Vödrös D, Thorstensson R, Doms RW, Fenyö EM, Reeves JD. (2003) Evolution of coreceptor use and CD4-independence in envelope clones derived from SIVsm-infected macaques. Virology316 (1): 17-28. [PMID:14599787]

51. Wan ES, Qiu W, Baccarelli A, Carey VJ, Bacherman H, Rennard SI, Agusti A, Anderson W, Lomas DA, Demeo DL. (2012) Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome. Hum. Mol. Genet.21 (13): 3073-82. [PMID:22492999]

52. Weiler A, May GE, Qi Y, Wilson N, Watkins DI. (2006) Polymorphisms in eight host genes associated with control of HIV replication do not mediate elite control of viral replication in SIV-infected Indian rhesus macaques. Immunogenetics58 (12): 1003-9. [PMID:17106666]

53. Xiao L, Rudolph DL, Owen SM, Spira TJ, Lal RB. (1998) Adaptation to promiscuous usage of CC and CXC-chemokine coreceptors in vivo correlates with HIV-1 disease progression. AIDS12 (13): F137-43. [PMID:9764773]

54. Yang C, Yang Q, Compans RW. (2000) Coreceptor-dependent inhibition of the cell fusion activity of simian immunodeficiency virus Env proteins. J. Virol.74 (13): 6217-22. [PMID:10846110]

55. Zhang L, He T, Huang Y, Chen Z, Guo Y, Wu S, Kunstman KJ, Brown RC, Phair JP, Neumann AU et al.. (1998) Chemokine coreceptor usage by diverse primary isolates of human immunodeficiency virus type 1. J. Virol.72 (11): 9307-12. [PMID:9765480]

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Anthony P. Davenport, Stephen Alexander, Joanna L. Sharman, Adam J. Pawson, Helen E. Benson, Amy E. Monaghan, Wen Chiy Liew, Chido Mpamhanga, Jim Battey, Richard V. Benya, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis, Eliot Spindel, Laura Storjohann, Kalyan Tirupula, Tom I. Bonner, Richard Neubig, Jean-Philippe Pin, Michael Spedding, Anthony Harmar.
Class A Orphans: GPR15. Last modified on 14/03/2017. Accessed on 20/11/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=87.