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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 361 | 13q32.3 | GPR183 | G protein-coupled receptor 183 | |
| Mouse | 7 | 357 | 14 E5 | Gpr183 | G protein-coupled receptor 183 | |
| Rat | 7 | 357 | 15q25 | Gpr183 | G protein-coupled receptor 183 | |
| Previous and Unofficial Names |
| EBI2 | Epstein-Barr virus-induced gene 2 | EBV-induced G protein-coupled receptor 2 | G protein-coupled receptor 183 | lymphocyte-specific G protein-coupled receptor |
| Database Links |
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| Specialist databases | |
| GPCRdb | gp183_human (Hs), gp183_mouse (Mm), gp183_rat (Rn) |
| Other databases | |
| Alphafold | P32249 (Hs), Q3U6B2 (Mm), D4A7K7 (Rn) |
| ChEMBL Target | CHEMBL3259470 (Hs), CHEMBL3259471 (Mm), CHEMBL4802001 (Rn) |
| Ensembl Gene | ENSG00000169508 (Hs), ENSMUSG00000051212 (Mm), ENSRNOG00000025094 (Rn) |
| Entrez Gene | 1880 (Hs), 321019 (Mm), 679975 (Rn) |
| Human Protein Atlas | ENSG00000169508 (Hs) |
| KEGG Gene | hsa:1880 (Hs), mmu:321019 (Mm), rno:679975 (Rn) |
| OMIM | 605741 (Hs) |
| Pharos | P32249 (Hs) |
| RefSeq Nucleotide | NM_004951 (Hs), NM_183031 (Mm), NM_001109386 (Rn) |
| RefSeq Protein | NP_004942 (Hs), NP_898852 (Mm), NP_001102856 (Rn) |
| UniProtKB | P32249 (Hs), Q3U6B2 (Mm), D4A7K7 (Rn) |
| Wikipedia | GPR183 (Hs) |
| Natural/Endogenous Ligands |
| 7α,27-dihydroxycholesterol |
| 7β, 27-dihydroxycholesterol |
| 7β, 25-dihydroxycholesterol |
| 7α,25-dihydroxycholesterol |
| 27-hydroxycholesterol |
| 25-hydroxycholesterol |
| 7α-hydroxycholesterol |
| 7β-hydroxycholesterol |
| Oxysterols |
| Comments: Proposed ligands, two independent publications |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The pharmacological characterisation of different oxysterols have been conducted, and 7α25-dihydroxycholesterol (7α,25-OHC) was found to be the most potent and selective agonist of GPR183, with its presence in tissues confirmed by mass spectrometry [9,12]. Blocking the synthesis of 7α,25-OHC in vivo with clotrimazole, a CYP7B1 inhibitor, reduced the content of 7α,25-OHC in the mouse spleen and promoted the migration of adoptively transferred pre-activated B cells to the T/B boundary (the boundary between the T-zone and B-zone in the spleen follicle), mimicking the phenotype of pre-activated B cells from EBI2-deficient mice [9]. GPR183 ligand activity is reported to be concentrated in the splenic reticular network [7]. However, Kelly et al. reported that GPR183 ligand activity was found in lymphoid (spleen, lymph nodes and thymus ) and nonlymphoid tissues (brain, kidney, liver and lung) [11]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Immunopharmacology Comments |
| Gpr183-deficient mice show a 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 [11,13]. This is suggested to position B cells in the correct location for mounting T-dependent antibody responses. GPR183 is induced during Epstein-Barr virus infection [5]. |
| Immuno Process Associations | ||
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| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
| Gi/Go family | Adenylyl cyclase inhibition |
| References: 9,11-12,15 | |
| Tissue Distribution
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| Tissue Distribution Comments | ||||||||
| It was reported that GPR183 is expressed human B-lymphocytes cell lines and lymphoid tissues but not in T-lymphocytes cell lines when examined by Northern blot analysis [4]. However, GPR183 was reported to be expressed in T lymphocytes when examined using RT-PCR [15]. GPR183 is highly expressed in Epstein-Barr virus-infected cells during latent and lytic infection [15]. | ||||||||
| Expression Datasets |
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| Physiological Functions
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| Physiological Functions Comments | ||||||||
| Germinal central B cell differentiation is associated with downregulation of GPR183 via transciption repression of Bcl-6 [16]. It was later reported that GPR183 deficiency does not prevent the normal germinal centre formation [13]. GPR183-dependent movement of activated B cells to the outer follicle coincides with CCR7 downregulation and is promoted by CD40 engagement [11]. | ||||||||
| Physiological Consequences of Altering Gene Expression
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| Physiological Consequences of Altering Gene Expression Comments | ||||||||||
| Analysis of knockout mice deficient in expression of GPR183, CXCR5, or CCR7 revealed that the expression of all three of these receptors is needed to direct B cells movement in the steady state and during immune responses [7]. However, B cell migration mediated by GPR183 toward outer follicles is reported to be independent of both CXCR5 and CCR7 [7]. | ||||||||||
| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Gene Expression and Pathophysiology Comments | |
| It is reported that GPR183 was significantly overexpressed in the metastatic sites (subcutis, regional lymph node and brain) [14]. Polymorphisms in human GPR183 gene were associated with type I diabetes and other inflammatory diseases [10-11]. Polymorphisms in the GPR183 promoter were linked to differences in the inflammotory state of some organs, such as kidney, liver and pancreas [10-11]. |
| Biologically Significant Variants
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| General Comments |
| GPR183 is induced during Epstein-Barr Virus infection [5]. The activity of GPR183 is regulated by at least two regions with PheVI:13 (Phe257) and the neighbouring residues acting as negative regulators, and ArgII:20 (Arg87)acting as a positive regulator [2]. |
1. Amisten S, Braun OO, Bengtsson A, Erlinge D. (2008) Gene expression profiling for the identification of G-protein coupled receptors in human platelets. Thromb Res, 122 (1): 47-57. [PMID:17920662]
2. Benned-Jensen T, Rosenkilde MM. (2008) Structural motifs of importance for the constitutive activity of the orphan 7TM receptor EBI2: analysis of receptor activation in the absence of an agonist. Mol Pharmacol, 74 (4): 1008-21. [PMID:18628402]
3. Benned-Jensen T, Smethurst C, Holst PJ, Page KR, Sauls H, Sivertsen B, Schwartz TW, Blanchard A, Jepras R, Rosenkilde MM. (2011) Ligand modulation of the Epstein-Barr virus-induced seven-transmembrane receptor EBI2: identification of a potent and efficacious inverse agonist. J Biol Chem, 286 (33): 29292-29302. [PMID:21673108]
4. Birkenbach M, Josefsen K, Yalamanchili R, Lenoir G, Kieff E. (1993) Epstein-Barr virus-induced genes: first lymphocyte-specific G protein-coupled peptide receptors. J Virol, 67 (4): 2209-20. [PMID:8383238]
5. Cahir-McFarland ED, Carter K, Rosenwald A, Giltnane JM, Henrickson SE, Staudt LM, Kieff E. (2004) Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells. J Virol, 78 (8): 4108-19. [PMID:15047827]
6. Gatto D, Paus D, Basten A, Mackay CR, Brink R. (2009) Guidance of B cells by the orphan G protein-coupled receptor EBI2 shapes humoral immune responses. Immunity, 31 (2): 259-69. [PMID:19615922]
7. Gatto D, Wood K, Brink R. (2011) EBI2 operates independently of but in cooperation with CXCR5 and CCR7 to direct B cell migration and organization in follicles and the germinal center. J Immunol, 187 (9): 4621-8. [PMID:21948984]
8. Gessier F, Preuss I, Yin H, Rosenkilde MM, Laurent S, Endres R, Chen YA, Marsilje TH, Seuwen K, Nguyen DG et al.. (2014) Identification and characterization of small molecule modulators of the Epstein-Barr virus-induced gene 2 (EBI2) receptor. J Med Chem, 57 (8): 3358-68. [PMID:24678947]
9. Hannedouche S, Zhang J, Yi T, Shen W, Nguyen D, Pereira JP, Guerini D, Baumgarten BU, Roggo S, Wen B et al.. (2011) Oxysterols direct immune cell migration via EBI2. Nature, 475 (7357): 524-7. [PMID:21796212]
10. Heinig M, Petretto E, Wallace C, Bottolo L, Rotival M, Lu H, Li Y, Sarwar R, Langley SR, Bauerfeind A, Hummel O, Lee YA, Paskas S, Rintisch C, Saar K, Cooper J, Buchan R, Gray EE, Cyster JG, Cardiogenics Consortium, Erdmann J, Hengstenberg C, Maouche S, Ouwehand WH, Rice CM, Samani NJ, Schunkert H, Goodall AH, Schulz H, Roider HG, Vingron M, Blankenberg S, Münzel T, Zeller T, Szymczak S, Ziegler A, Tiret L, Smyth DJ, Pravenec M, Aitman TJ, Cambien F, Clayton D, Todd JA, Hubner N, Cook SA. (2010) A trans-acting locus regulates an anti-viral expression network and type 1 diabetes risk. Nature, 467 (7314): 460-4. [PMID:20827270]
11. Kelly LM, Pereira JP, Yi T, Xu Y, Cyster JG. (2011) EBI2 guides serial movements of activated B cells and ligand activity is detectable in lymphoid and nonlymphoid tissues. J Immunol, 187 (6): 3026-32. [PMID:21844396]
12. Liu C, Yang XV, Wu J, Kuei C, Mani NS, Zhang L, Yu J, Sutton SW, Qin N, Banie H et al.. (2011) Oxysterols direct B-cell migration through EBI2. Nature, 475 (7357): 519-23. [PMID:21796211]
13. 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]
14. Qin Y, Verdegaal EM, Siderius M, Bebelman JP, Smit MJ, Leurs R, Willemze R, Tensen CP, Osanto S. (2011) 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 (1): 207-18. [PMID:20880198]
15. Rosenkilde MM, Benned-Jensen T, Andersen H, Holst PJ, Kledal TN, Lüttichau HR, Larsen JK, Christensen JP, Schwartz TW. (2006) Molecular pharmacological phenotyping of EBI2. An orphan seven-transmembrane receptor with constitutive activity. J Biol Chem, 281 (19): 13199-208. [PMID:16540462]
16. Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM. (2000) BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity, 13 (2): 199-212. [PMID:10981963]
17. Xi J, Gong H, Li Z, Li Y, Wu Y, Zhang Y, Wang JF, Fan GH. (2023) Discovery of a First-in-Class GPR183 Antagonist for the Potential Treatment of Rheumatoid Arthritis. J Med Chem, 66 (23): 15926-15943. [PMID:38047891]
target has curated data in GtoImmuPdb
