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Target not currently curated in GtoImmuPdb

Target id: 199

Nomenclature: ADGRA3

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 1321 4p15.31 ADGRA3 adhesion G protein-coupled receptor A3 19
Mouse 7 1449 5 B3 Adgra3 adhesion G protein-coupled receptor A3
Rat 7 1455 14q11 Adgra3 adhesion G protein-coupled receptor A3
Previous and Unofficial Names
TEM5L | TEM5-like | PGR21 | GPR125 (G protein-coupled receptor 125)
Database Links
Specialist databases
GPCRDB agra3_human (Hs), agra3_mouse (Mm)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
RefSeq Nucleotide
RefSeq Protein
Agonist Comments
No ligands identified: orphan receptor.
Primary Transduction Mechanisms
Transducer Effector/Response
G protein (identity unknown)
Comments:  Predicted to transduce signal through G proteins based on sequence signatures [5]. However, studies on several different adhesion GPCRs have provided evidence that these receptors are in fact authentic G protein-coupled receptors. Adhesion GPCRs with experimentally verified G-protein coupling includes ADGRG1 [9], ADGRD1 [4] and ADGRG6 [12]. Recent reviews [14] and adhesion GPCR consortium meeting report [1] addressed the issues to unravel the signal transduction of adhesion GPCRs and provided further preliminary evidences [6] for other adhesion GPCRs to transduce signal through G proteins.
Secondary Transduction Mechanisms
Transducer Effector/Response
G protein (identity unknown)
Tissue Distribution
Skeletal muscle, prostate, testis, colon >> heart, placenta, pancreas, small intestine > brain, spleen, thymus. Not detected in lung or white blood cells.
Species:  Human
Technique:  Northern blotting.
References:  19
High expression in skeletal muscle, prostate, testis and colon, low expression in heart, placenta and small intestine, present in various human tumors of breast, esophagus, stomach, liver, kidney, small intestine, colon, ovary, fallopian tube, uterus
Species:  Human
Technique:  Northern blot and RT-PCR
References:  19
Species:  Human
Technique:  Immunohistochemistry and Western blot.
References:  7
Lung, liver, kidney, pancreas, cortex, hypothalamus, hippocampus, thalamus, colliculus, cerebellum, olfactory bulb
Species:  Mouse
Technique:  In situ hybridisation
References:  15
Seminiferous tubules, germ cells, spermatogonial progenitor cells (SPCs) spermatogonial-derived stem cells (MASCs)
Species:  Mouse
Technique:  Immunohistochemistry and RT-PCR
References:  8,18
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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Functional Assays
ADGRA3-positive spermatogonia proliferated, indicating that ADGRA3-positive spermatogonia possess the proliferative features of human spermatogonial stem cells and progenitors
Species:  Human
Tissue:  Spermatogonia
Response measured:  Proliferation
References:  7
Physiological Functions
Has a role in repopulating spermatogonial stem cells (SSCs) in the adult human testes
Species:  Human
Tissue:  Testis
References:  10
May have a role in the development of spermatogonia, predicted to have a role in germ cell development
Species:  Mouse
Tissue:  Testis
References:  18
Plays a functional role in choroidal and hippocampal response to injury
Species:  Mouse
Tissue:  Choroid plexus
References:  15
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr125tm1Rafi Gpr125tm1Rafi/Gpr125tm1Rafi
involves: C57BL/6J
MGI:1917943  MP:0002169 no abnormal phenotype detected PMID: 17882221 
Biologically Significant Variants
Type:  Splice variant
Species:  Human
Description:  The physiological effect of this variant is unknown
Amino acids:  1321
Nucleotide accession: 
Protein accession: 
References:  3
General Comments
ADGRA3 (formerly GPR125) is an orphan receptor that belongs to Family III Adhesion-GPCRs along with ADGRA1 (GPR123) and ADGRA2 (GPR124) [2]. The gene is localized on human chromosome 4 and mouse chromosome 5. Phylogenetic analysis suggests that ADGRA1-3 share a common ancestor suggesting the evolution from an ancestral gene through gene duplication [2]. Deuterostome invertebrates like ciona, amphioxus, sea urchin and acorn worms contain a single copy that is very similar to ADGRA1-3 [11,13,16] indicating a gene duplication event at the emergence of vertebrates. As of now no direct function has been attributed to these receptors, however, GPR125 is useful as a potential stem and progenitor cell surface marker and therefore represents a novel target for purifying adult stem and progenitors from tissues, with the goal of developing autologous multipotent cell lines [17-18]. ADGRA3 is strongly expressed in the testis and the prostate and were predicted to have a role in development of spermatogonia and also a possible role role in germ cell development [10,17-18]. ADGRA3 in human is 1321 amino acids long and it is very similar to ADGRA2 in domain organisation. ADGRA3 has a GPCR proteolysis site (GPS), Ig-like domain and LRR repeats in the N terminus. A functional splice variant for ADGRA3 in human was found and it seems that the splice variant was found to be conserved in other species including mouse [3].


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1. Araç D, Aust G, Calebiro D, Engel FB, Formstone C, Goffinet A, Hamann J, Kittel RJ, Liebscher I, Lin HH et al.. (2012) Dissecting signaling and functions of adhesion G protein-coupled receptors. Ann. N. Y. Acad. Sci., 1276: 1-25. [PMID:23215895]

2. Bjarnadóttir TK, Fredriksson R, Höglund PJ, Gloriam DE, Lagerström MC, Schiöth HB. (2004) The human and mouse repertoire of the adhesion family of G-protein-coupled receptors. Genomics, 84 (1): 23-33. [PMID:15203201]

3. 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]

4. Bohnekamp J, Schöneberg T. (2011) Cell adhesion receptor GPR133 couples to Gs protein. J. Biol. Chem., 286 (49): 41912-6. [PMID:22025619]

5. 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]

6. Gupte J, Swaminath G, Danao J, Tian H, Li Y, Wu X. (2012) Signaling property study of adhesion G-protein-coupled receptors. FEBS Lett., 586 (8): 1214-9. [PMID:22575658]

7. He Z, Kokkinaki M, Jiang J, Dobrinski I, Dym M. (2010) Isolation, characterization, and culture of human spermatogonia. Biol. Reprod., 82 (2): 363-72. [PMID:19846602]

8. He Z, Kokkinaki M, Jiang J, Zeng W, Dobrinski I, Dym M. (2012) Isolation of human male germ-line stem cells using enzymatic digestion and magnetic-activated cell sorting. Methods Mol. Biol., 825: 45-57. [PMID:22144235]

9. Iguchi T, Sakata K, Yoshizaki K, Tago K, Mizuno N, Itoh H. (2008) Orphan G protein-coupled receptor GPR56 regulates neural progenitor cell migration via a G alpha 12/13 and Rho pathway. J. Biol. Chem., 283 (21): 14469-78. [PMID:18378689]

10. Izadyar F, Wong J, Maki C, Pacchiarotti J, Ramos T, Howerton K, Yuen C, Greilach S, Zhao HH, Chow M et al.. (2011) Identification and characterization of repopulating spermatogonial stem cells from the adult human testis. Hum. Reprod., 26 (6): 1296-306. [PMID:21349855]

11. Kamesh N, Aradhyam GK, Manoj N. (2008) The repertoire of G protein-coupled receptors in the sea squirt Ciona intestinalis. BMC Evol. Biol., 8: 129. [PMID:18452600]

12. Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB, Talbot WS. (2009) A G protein-coupled receptor is essential for Schwann cells to initiate myelination. Science, 325 (5946): 1402-5. [PMID:19745155]

13. Nordström KJ, Fredriksson R, Schiöth HB. (2008) The amphioxus (Branchiostoma floridae) genome contains a highly diversified set of G protein-coupled receptors. BMC Evol. Biol., 8: 9. [PMID:18199322]

14. Paavola KJ, Hall RA. (2012) Adhesion G protein-coupled receptors: signaling, pharmacology, and mechanisms of activation. Mol. Pharmacol., 82 (5): 777-83. [PMID:22821233]

15. Pickering C, Hägglund M, Szmydynger-Chodobska J, Marques F, Palha JA, Waller L, Chodobski A, Fredriksson R, Lagerström MC, Schiöth HB. (2008) The Adhesion GPCR GPR125 is specifically expressed in the choroid plexus and is upregulated following brain injury. BMC Neurosci, 9: 97. [PMID:18834514]

16. Raible F, Tessmar-Raible K, Arboleda E, Kaller T, Bork P, Arendt D, Arnone MI. (2006) Opsins and clusters of sensory G-protein-coupled receptors in the sea urchin genome. Dev. Biol., 300 (1): 461-75. [PMID:17067569]

17. Seandel M, Falciatori I, Shmelkov SV, Kim J, James D, Rafii S. (2008) Niche players: spermatogonial progenitors marked by GPR125. Cell Cycle, 7 (2): 135-40. [PMID:18256534]

18. Seandel M, James D, Shmelkov SV, Falciatori I, Kim J, Chavala S, Scherr DS, Zhang F, Torres R, Gale NW et al.. (2007) Generation of functional multipotent adult stem cells from GPR125+ germline progenitors. Nature, 449 (7160): 346-50. [PMID:17882221]

19. Yamamoto Y, Irie K, Asada M, Mino A, Mandai K, Takai Y. (2004) Direct binding of the human homologue of the Drosophila disc large tumor suppressor gene to seven-pass transmembrane proteins, tumor endothelial marker 5 (TEM5), and a novel TEM5-like protein. Oncogene, 23 (22): 3889-97. [PMID:15021905]


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