ADGRG2 | Adhesion Class GPCRs | IUPHAR Guide to IMMUNOPHARMACOLOGY

Top ▲

ADGRG2

Target not currently curated in GtoImmuPdb

Target id: 187

Nomenclature: ADGRG2

Family: Adhesion Class GPCRs

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

Gene and Protein Information
Adhesion G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 1017 Xp22.13 ADGRG2 adhesion G protein-coupled receptor G2 14
Mouse 7 1009 X F4 Adgrg2 adhesion G protein-coupled receptor G2 13
Rat 7 1013 Xq21 Adgrg2 adhesion G protein-coupled receptor G2 13
Previous and Unofficial Names
GPR64 (G protein-coupled receptor 64) | HE6 (human epididymal 6)
Database Links
Specialist databases
GPCRDB agrg2_human (Hs), agrg2_mouse (Mm), agrg2_rat (Rn)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Agonist Comments
No ligands identified: orphan receptor.
Primary Transduction Mechanisms
Transducer Effector/Response
Adenylate cyclase stimulation
Comments:  This pathway applies to the recombinant expression of human ADGRG2 protein in Xenopus melanophores [6]. There is a brief note in the literature that the receptor will activate G proteins Gs and Gq when overexpressed in Xenopus melanophores (C. Jayawickreme, pers. communication, cited in [6]) which couple to adenylate cyclase and phospholipase C, respectively (see below).
References:  10
Secondary Transduction Mechanisms
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
Comments:  This pathway also applies to the recombinant expression of human ADGRG2 protein in Xenopus melanophores [1] (see above).
References: 
Tissue Distribution
Ewing sarcoma
Species:  Human
Technique:  Microarray analysis and RT-PCR
References:  15
Rheumatoid synovial fibroblasts
Species:  Human
Technique:  Microarray analysis
References:  9
Microarray analyses (Affymetrix chips) of essentially all human tissues and organs revealed a highly epididymis-restricted expression.
Species:  Human
Technique:  Microarray analysis.
References:  10
Epididymis, highly expressed in ductuli efferentes, expressed less strongly in distal caput and corpus, not expressed in cauda
Species:  Human
Technique:  Northern blot and EST, microarray analysis, in situ hybridisation, Western blot and immunohistrochemistry
References:  2,10-11,13-14
Epididymus specific.
Species:  Human
Technique:  Northern blotting.
References:  14
Epididymis, maximum expression in the initial segment of the caput, less intense in efferent ducts, colocalization with apical and subapical F-actin scaffold in male excurrent duct epithelia
Species:  Mouse
Technique:  Northern blot, Western blot and immunohistochemistry
References:  11,13
Almost exclusively in proximal epididymis. Faint signals in spleen and brain after prolonged exposure. No signal in heart, liver, kidney, lung, whole embryo, testis.
Species:  Mouse
Technique:  Northern blotting.
References:  13
Epididymis
Species:  Rat
Technique:  Western blot
References:  13
Tissue Distribution Comments
ADGRG2 is also specific to certain cell types, namely the non-ciliated principal cells in the ductuli efferentes [11]. It is not expressed in the neighbouring ciliated cells. In the Ductuli efferentes and proximal epididymal duct, the mature receptor is a heterodimeric membrane protein of the apical epithelial membrane domain [13].
Expression Datasets

Show »

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!
Functional Assays
ADGRG2 knockdown suppresses invasive and metastasis of Ewing carcinomas
Species:  Mouse
Tissue:  Liver, lung
Response measured:  Tumour suppression
References:  15
Physiological Functions
Control of water balance and fluid reabsorption in the male excurrent ducts
Species:  Mouse
Tissue:  Excurrent ducts
References:  3
Post-testicular sperm maturation
Species:  Human
Tissue:  Epididymis
References:  14
Control of protein expression (see comments below)
Species:  Mouse
Tissue:  Caput epididymidis
References:  4
Physiological Functions Comments
KO mice show a downregulation of the following genes: Enpp2/autotaxin, the lipocalins 8 and 9, the beta-defensin Defb42, cystatins 8 and 12, as well as the membrane proteins ADAM (a disintegrin and metalloprotease) 28, claudin-10, EAAC1, and Me9 (Teddm1). In contrast, clusterin/ApoJ and osteopontin/Spp1 mRNAsare are upregulated in KO tissue [4].
Physiological Consequences of Altering Gene Expression
Mice show epididymal fluid dysregulation, sperm stasis, and male infertility, hemizygous mice have decreased fertility
Species:  Mouse
Tissue:  Full-body knockout
Technique:  Gene knockouts
References:  3
Targeted deletion of the 7TM domain of the murine Adgrg2 gene results in male infertility. Mutant mice reveal a dysregulation of fluid reabsorbtion within the efferent ductules, leading to a backup of fluid accumulation in the testis and a subsequent stasis of spermatozoa within the efferent ducts. Note that this deletion may not affect the expression of the large extracellualr domain.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  3,10
Phenotypes, Alleles and Disease Models Mouse data from MGI

Show »

Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0002662 abnormal cauda epididymis morphology PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0001784 abnormal fluid regulation PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0001156 abnormal spermatogenesis PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0009234 absent sperm head PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0002675 asthenozoospermia PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0004929 decreased epididymis weight PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0009140 dilated efferent ductules of testis PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0009257 dilated seminiferous tubules PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0001148 enlarged testes PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0009237 kinked sperm flagellum PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0002687 oligozoospermia PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0001922 reduced male fertility PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0004930 small epididymis PMID: 15367682 
Gpr64tm1Bend Gpr64tm1Bend/Y
involves: 129P2/OlaHsd * C57BL/6
MGI:2446854  MP:0005578 teratozoospermia PMID: 15367682 
Gene Expression and Pathophysiology Comments
By extrapolation from the KO phenotype, ADGRG2 may be associated with some cases of unexplained male infertility.
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Description:  Physiological effect unknown
Amino acids:  1017
Nucleotide accession: 
Protein accession: 
References:  13-14
Type:  Splice variant
Species:  Human
Description:  Physiological effect unknown
Amino acids:  1003
Nucleotide accession: 
Protein accession: 
References:  13-14
Type:  Splice variant
Species:  Human
Description:  Physiological effect unknown
Amino acids:  995
Nucleotide accession: 
Protein accession: 
References:  13-14
Type:  Splice variant
Species:  Human
Description:  Physiological effect unknown
Amino acids:  1014
Nucleotide accession: 
Protein accession: 
References:  13-14
Type:  Splice variant
Species:  Human
Description:  Physiological effect unknown
Amino acids:  1001
Nucleotide accession: 
Protein accession: 
References:  13-14
Type:  Splice variant
Species:  Human
Description:  Physiological effect unknown
Amino acids:  966
Nucleotide accession: 
Protein accession: 
References:  13-14
Type:  Splice variant
Species:  Human
Description:  Physiological effect unknown
Amino acids:  979
Nucleotide accession: 
Protein accession: 
References:  13-14
Type:  Splice variant
Species:  Human
Description:  Physiological effect unknown
Amino acids:  993
Nucleotide accession: 
Protein accession: 
References:  13-14
Biologically Significant Variant Comments
The human ADGRG2 gene was assigned to the X chromosome (Xp22.13) in a region which is syntenic to the mouse [13]. Three DNA variants (single nucleotide polymorphisms) of the human gene sequence have been reported [16] which are listed in the LOVD X-chromosome gene database. 10 transcripts exist in human [5,13-14]. The transcripts affect predominantly the open reading frame in the N-terminal part immediately following the signal peptide. Nine of the transcripts encode proteins which differ in length.
General Comments
ADGRG2 (adhesion G protein-coupled receptor G2, formerly GPR64) is an orphan receptor belonging to Family VIII Adhesion-GPCRs together with ADGRG1 and ADGRG3-7 [7]. The gene is localized on human chromosome X and mouse chromosome 8. The long extracellular ectosubunit of ADGRG2 is highly glycosylated [13], showing similarity to mucin-like cell-surface molecules.

Gene product appears to be cleaved shortly before the first transmembrane domain to produce a large, highly glycoslylated (approximately 180 kDa) amino terminal domain and carboxly terminal domain containing seven transmemberane domains (40 kDa in human) [13]. The putative cysteine-rich cleavage site, GPS (GPCR proteolysis site), is found in several other class B GPCRs [8].

Full coding sequence human cDNA is publicly available, IMAGE:7447877 [12] in mammalian expression vector pCDNA3.1.

References

Show »

1. Aalto Y, El-Rifa W, Vilpo L, Ollila J, Nagy B, Vihinen M, Vilpo J, Knuutila S. (2001) Distinct gene expression profiling in chronic lymphocytic leukemia with 11q23 deletion. Leukemia, 15 (11): 1721-8. [PMID:11681413]

2. Bjarnadóttir TK, Geirardsdóttir K, Ingemansson M, Mirza MA, Fredriksson R, Schiöth HB. (2007) Identification of novel splice variants of Adhesion G protein-coupled receptors. Gene, 387 (1-2): 38-48. [PMID:17056209]

3. Davies B, Baumann C, Kirchhoff C, Ivell R, Nubbemeyer R, Habenicht UF, Theuring F, Gottwald U. (2004) Targeted deletion of the epididymal receptor HE6 results in fluid dysregulation and male infertility. Mol. Cell. Biol., 24 (19): 8642-8. [PMID:15367682]

4. Davies B, Behnen M, Cappallo-Obermann H, Spiess AN, Theuring F, Kirchhoff C. (2007) Novel epididymis-specific mRNAs downregulated by HE6/Gpr64 receptor gene disruption. Mol. Reprod. Dev., 74 (5): 539-53. [PMID:17034053]

5. Flicek P, Ahmed I, Amode MR, Barrell D, Beal K, Brent S, Carvalho-Silva D, Clapham P, Coates G, Fairley S et al.. (2013) Ensembl 2013. Nucleic Acids Res., 41 (Database issue): D48-55. [PMID:23203987]

6. Foord SM, Jupe S, Holbrook J. (2002) Bioinformatics and type II G-protein-coupled receptors. Biochem. Soc. Trans., 30 (4): 473-9. [PMID:12196118]

7. Fredriksson R, Gloriam DE, Höglund PJ, Lagerström MC, Schiöth HB. (2003) There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini. Biochem. Biophys. Res. Commun., 301 (3): 725-34. [PMID:12565841]

8. Fredriksson R, Lagerström MC, Höglund PJ, Schiöth HB. (2002) Novel human G protein-coupled receptors with long N-terminals containing GPS domains and Ser/Thr-rich regions. FEBS Lett., 531 (3): 407-14. [PMID:12435584]

9. Galligan CL, Baig E, Bykerk V, Keystone EC, Fish EN. (2007) Distinctive gene expression signatures in rheumatoid arthritis synovial tissue fibroblast cells: correlates with disease activity. Genes Immun., 8 (6): 480-91. [PMID:17568789]

10. Gottwald U, Davies B, Fritsch M, Habenicht UF. (2006) New approaches for male fertility control: HE6 as an example of a putative target. Mol. Cell. Endocrinol., 250 (1-2): 49-57. [PMID:16442214]

11. Kirchhoff C, Osterhoff C, Samalecos A. (2008) HE6/GPR64 adhesion receptor co-localizes with apical and subapical F-actin scaffold in male excurrent duct epithelia. Reproduction, 136 (2): 235-45. [PMID:18469038]

12. Lennon G, Auffray C, Polymeropoulos M, Soares MB. (1996) The I.M.A.G.E. Consortium: an integrated molecular analysis of genomes and their expression. Genomics, 33 (1): 151-2. [PMID:8617505]

13. Obermann H, Samalecos A, Osterhoff C, Schröder B, Heller R, Kirchhoff C. (2003) HE6, a two-subunit heptahelical receptor associated with apical membranes of efferent and epididymal duct epithelia. Mol. Reprod. Dev., 64 (1): 13-26. [PMID:12420295]

14. Osterhoff C, Ivell R, Kirchhoff C. (1997) Cloning of a human epididymis-specific mRNA, HE6, encoding a novel member of the seven transmembrane-domain receptor superfamily. DNA Cell Biol., 16 (4): 379-89. [PMID:9150425]

15. Richter GH, Fasan A, Hauer K, Grunewald TG, Berns C, Rössler S, Naumann I, Staege MS, Fulda S, Esposito I et al.. (2013) G-Protein coupled receptor 64 promotes invasiveness and metastasis in Ewing sarcomas through PGF and MMP1. J. Pathol., 230 (1): 70-81. [PMID:23338946]

16. Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, O'Meara S, Latimer C, Dicks E, Menzies A et al.. (2009) A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat. Genet., 41 (5): 535-43. [PMID:19377476]

Contributors

Show »

How to cite this page

Select citation format: