Nomenclature: GPR183

Family: Class A Orphans

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

Contents

Gene and Protein Information
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
EBV-induced G-protein coupled receptor 2
EBI2
Epstein-Barr virus-induced gene 2
lymphocyte-specific G protein-coupled receptor
EBV-induced G protein-coupled receptor 2
GPR183
Epstein-Barr virus induced gene 2 (lymphocyte-specific G protein-coupled receptor)
LOC679975
G protein-coupled receptor 183
G-protein coupled receptor 183
similar to EBV-induced G-protein coupled receptor 2 (EBI2)
Database Links
Ensembl Gene
Entrez Gene
GPCRDB
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
Human Protein Reference Database
InterPro
KEGG Gene
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniGene Hs.
UniProtKB
Wikipedia
Natural/Endogenous Ligands
7α,25-dihydroxycholesterol
Oxysterols
Comments: Proposed ligands, two independent publications
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
7α,25-dihydroxycholesterol Hs Full agonist 8.1 – 9.85 pEC50 7,10
pEC50 8.1 – 9.85 (EC50 8x10-9 – 1.4x10-10 M) [7,10]
7α,27-dihydroxycholesterol Hs Agonist 8.89 pEC50 10
pEC50 8.89 (EC50 1.3x10-9 M) [10]
7β, 25-dihydroxycholesterol Hs Agonist 8.68 pEC50 10
pEC50 8.68 (EC50 2.1x10-9 M) [10]
7β, 27-dihydroxycholesterol Hs Agonist 7.29 pEC50 10
pEC50 7.29 (EC50 5.1x10-8 M) [10]
7α-hydroxycholesterol Hs Agonist 7.09 pEC50 10
pEC50 7.09 (EC50 8.2x10-8 M) [10]
25-hydroxycholesterol Hs Agonist 6.9 pEC50 10
pEC50 6.9 (EC50 1.27x10-7 M) [10]
7β-hydroxycholesterol Hs Agonist 5.75 pEC50 10
pEC50 5.75 (EC50 1.763x10-6 M) [10]
27-hydroxycholesterol Hs Agonist 5.52 pEC50 10
pEC50 5.52 (EC50 3.029x10-6 M) [10]
7α,25-dihydroxycholesterol Hs Full agonist 7.15 – 9.62 pIC50 7,10
pIC50 7.15 – 9.62 (IC50 7x10-8 – 2.42x10-10 M) [7,10]
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 [7,10]. 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 [7]. GPR183 ligand activity is reported to be concentrated in the splenic reticular network [6]. 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) [9].
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
References:  7,9-10,13
Tissue Distribution
Highly expressed in myeloid cell types.
Species:  Human
Technique:  RT-PCR
References:  8
High expression in lymphoid tissues (peripheral blood mononuclear cells, lymph node and spleen) and lung tissue. Medium-to-high expression in aorta, right and left atrium, gastrointestinal tract (with the highest expression in appendix). Low-to-medium expression in urogenital system. Lowest expression in brain.
Species:  Human
Technique:  Multiple tissue expression array
References:  13
Highest expression in B-lymphocytes, followed by T-lymphocytes, NK cells and lowest in monocytes
Species:  Human
Technique:  RT-PCR
References:  13
Platelets
Species:  Human
Technique:  RT-PCR
References:  1
High expression in lung. Low expression in pancreas. No expression was detected in heart, brain, placenta, liver, skeletal muscle or kidney.
Species:  Human
Technique:  Northern blot
References:  3
Expressed in B-lymphocytes cell lines and in lymphoid tissues. Expressed at lower levels in a promyelocytic and histiocytic cell lines and in pulmonary tissue.
Species:  Human
Technique:  Northern blot
References:  3
Highly expressed in myeloid cell types.
Species:  Rat
Technique:  RT-PCR
References:  8
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 [3]. However, GPR183 was reported to be expressed in T lymphocytes when examined using RT-PCR [13]. GPR183 is highly expressed in Epstein-Barr virus-infected cells during latent and lytic infection [13].
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]

There should be a chart of expression data here, you may need to enable JavaScript!
Physiological Functions
Controls the localisation of activated B cells within lymphoid follicles in the early phase of B cell responses.
Species:  Mouse
Tissue:  Spleen
References:  6
Directs the immune cells (B cells, T cells or dendritic cells) expressing GPR183 in vitro and in vivo to interfollicular and outer follicular regions of secondary lymphoid organs.
Species:  Mouse
Tissue:  Secondary lymphoid organs
References:  7,9-10
Differential expression of GPR183 controls B cell localization within the follicles. Expression of GPR183 during early T cell-dependent antibody response is involved in migration of antigen-specific B cells to extracellular areas of B cells and differentiation into plasmablasts. In contrast, downregulation of GPR183 facillitates germinal centre B cell differentiation.
Species:  Mouse
Tissue:  Spleen
References:  5-6,11
Physiological Functions Comments
Germinal central B cell differentiation is associated with downregulation of GPR183 via transciption repression of Bcl-6 [14]. It was later reported that GPR183 deficiency does not prevent the normal germinal centre formation [11]. GPR183-dependent movement of activated B cells to the outer follicle coincides with CCR7 downregulation and is promoted by CD40 engagement [9].
Physiological Consequences of Altering Gene Expression
The bone-marrow-derived dendritic cells in GPR183-deficient mice do not migrate towards 7alpha,25-dihydroxycholesterol.
Species:  Mouse
Tissue:  Bone-marrow-derived dendritic cells
Technique:  Gene knockout
References:  7
GPR183 overexpression drives B cell location to the outer follicle.
Species:  Mouse
Tissue:  B cells
Technique:  Gene overexpression
References:  11
Rat macrophages with GPR183 knockdown have increased expression of interferon regulatory factor 7 Irf7.
Species:  Rat
Tissue:  Macrophages
Technique:  RNA interference
References:  8
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 stay in the follicle centre.
Species:  Mouse
Tissue:  Spleen
Technique:  Gene knockout
References:  9,11
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 [6]. However, B cell migration mediated by GPR183 toward outer follicles is reported to be independent of both CXCR5 and CCR7 [6].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr183tm1.2Rbr Gpr183tm1.2Rbr/Gpr183tm1.2Rbr
involves: C57BL/6 * FVB/N * SJL
MGI:2442034  MP:0002459 abnormal B cell physiology PMID: 19615922 
Gpr183tm1.2Rbr|Ightm1Rbr|Tg(IgkHyHEL10)1Rbr Gpr183tm1.2Rbr/Gpr183tm1.2Rbr,Ightm1Rbr/Ightm1Rbr,Tg(IgkHyHEL10)1Rbr/0
involves: C57BL/6 * FVB/N * SJL
MGI:2442034  MGI:3800404  MGI:96442  MP:0002459 abnormal B cell physiology PMID: 19615922 
Gpr183tm1.2Rbr|Ightm1Rbr|Tg(IgkHyHEL10)1Rbr Gpr183tm1.2Rbr/Gpr183tm1.2Rbr,Ightm1Rbr/Ightm1Rbr,Tg(IgkHyHEL10)1Rbr/0
involves: C57BL/6 * FVB/N * SJL
MGI:2442034  MGI:3800404  MGI:96442  MP:0005153 abnormal B cell proliferation PMID: 19615922 
Gpr183tm1.1Cys Gpr183tm1.1Cys/Gpr183tm1.1Cys
B6.129P2-Gpr183
MGI:2442034  MP:0008191 abnormal follicular B cell physiology PMID: 19597478 
Gpr183tm1.2Rbr|Ightm1Rbr|Tg(IgkHyHEL10)1Rbr Gpr183tm1.2Rbr/Gpr183tm1.2Rbr,Ightm1Rbr/Ightm1Rbr,Tg(IgkHyHEL10)1Rbr/0
involves: C57BL/6 * FVB/N * SJL
MGI:2442034  MGI:3800404  MGI:96442  MP:0005017 decreased B cell number PMID: 19615922 
Gpr183tm1.2Rbr|Ightm1Rbr|Tg(IgkHyHEL10)1Rbr Gpr183tm1.2Rbr/Gpr183tm1.2Rbr,Ightm1Rbr/Ightm1Rbr,Tg(IgkHyHEL10)1Rbr/0
involves: C57BL/6 * FVB/N * SJL
MGI:2442034  MGI:3800404  MGI:96442  MP:0008495 decreased IgG1 level PMID: 19615922 
Gpr183tm1.2Rbr|Ightm1Rbr|Tg(IgkHyHEL10)1Rbr Gpr183tm1.2Rbr/Gpr183tm1.2Rbr,Ightm1Rbr/Ightm1Rbr,Tg(IgkHyHEL10)1Rbr/0
involves: C57BL/6 * FVB/N * SJL
MGI:2442034  MGI:3800404  MGI:96442  MP:0001806 decreased IgM level PMID: 19615922 
Gpr183tm1.2Rbr Gpr183tm1.2Rbr/Gpr183tm1.2Rbr
involves: C57BL/6 * FVB/N * SJL
MGI:2442034  MP:0008098 decreased plasma cell number PMID: 19615922 
Gpr183tm1.2Rbr|Ightm1Rbr|Tg(IgkHyHEL10)1Rbr Gpr183tm1.2Rbr/Gpr183tm1.2Rbr,Ightm1Rbr/Ightm1Rbr,Tg(IgkHyHEL10)1Rbr/0
involves: C57BL/6 * FVB/N * SJL
MGI:2442034  MGI:3800404  MGI:96442  MP:0008098 decreased plasma cell number PMID: 19615922 
Gene Expression and Pathophysiology Comments
It is reported that GPR183 was significantly overexpressed in the metastatic sites (subcutis, regional lymph node and brain) [12]. Polymorphisms in human GPR183 gene were associated with type I diabetes and other inflammatory diseases [8-9]. Polymorphisms in the GPR183 promoter were linked to differences in the inflammotory state of some organs, such as kidney, liver and pancreas [8-9].
Biologically Significant Variants
Type:  Naturally occurring SNPs.
Species:  Human
Description:  C256F
SNP accession: 
General Comments
GPR183 is induced during Epstein-Barr Virus infection [4]. The activity of GPR13 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].
Available Assays
DiscoveRx PathHunter® CHO-K1 EBI2 β-Arrestin Cell Line (Cat no. 93-0437C2A)
PathHunter® eXpress EBI2 CHO-K1 β-Arrestin GPCR Assay (Cat no. 93-0437E2ACP21M)
more info

REFERENCES

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. 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]

4. 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]

5. 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. Immunity31 (2): 259-69. [PMID:19615922]

6. 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]

7. 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. Nature475 (7357): 524-7. [PMID:21796212]

8. 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. Nature467 (7314): 460-4. [PMID:20827270]

9. 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]

10. 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. Nature475 (7357): 519-23. [PMID:21796211]

11. Pereira JP, Kelly LM, Xu Y, Cyster JG. (2009) EBI2 mediates B cell segregation between the outer and centre follicle. Nature460 (7259): 1122-6. [PMID:19597478]

12. Qin Y, Verdegaal EM, Siderius M, Bebelman JP, Smit MJ, Leurs R, Willemze R, Tensen CP, Osanto S. (2010) 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,  [Epub ahead of print]. [PMID:20880198]

13. 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]

14. 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. Immunity13 (2): 199-212. [PMID:10981963]

To cite this database page, please use the following:

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: GPR183. Last modified on 01/08/2013. Accessed on 01/11/2014. IUPHAR database (IUPHAR-DB), http://www.iuphar-db.org/DATABASE/ObjectDisplayForward?objectId=81.

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