Contents:
Gene and Protein Information  |
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| Adhesion G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 560 | 10q26.3 | ADGRA1 | adhesion G protein-coupled receptor A1 | |
| Mouse | 7 | 578 | 7 F4 | Adgra1 | adhesion G protein-coupled receptor A1 | |
| Rat | 7 | 577 | 1q41 | Adgra1 | adhesion G protein-coupled receptor A1 | |
| Previous and Unofficial Names |
| GPR123 (G protein-coupled receptor 123) |
| Database Links |
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| Specialist databases | |
| GPCRdb | agra1_human (Hs) |
| Other databases | |
| Alphafold | Q86SQ6 (Hs) |
| ChEMBL Target | CHEMBL4523885 (Hs) |
| Ensembl Gene | ENSG00000197177 (Hs), ENSMUSG00000025475 (Mm), ENSRNOG00000054955 (Rn) |
| Entrez Gene | 84435 (Hs), 52389 (Mm), 309097 (Rn) |
| Human Protein Atlas | ENSG00000197177 (Hs) |
| KEGG Gene | hsa:84435 (Hs), mmu:52389 (Mm), rno:309097 (Rn) |
| OMIM | 612302 (Hs) |
| Pharos | Q86SQ6 (Hs) |
| RefSeq Nucleotide | NM_001083909 (Hs), NM_177469 (Mm) |
| RefSeq Protein | NP_001077378 (Hs), NP_803420 (Mm) |
| UniProtKB | Q86SQ6 (Hs) |
| Wikipedia | ADGRA1 (Hs) |
| Associated Protein Comments | ||
| Extracellular and transmembrane interactors: Reck [4,6,16], syndecan-1, -2 [5], integrin-αvβ3 [15], heparin [15]. Intracellular interactors: DLG1 [17]. |
| Agonist Comments | ||
| No ligands identified: orphan receptor. |
| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
| G protein (identity unknown) | |
| Comments: Principal transduction via dishevelled [6], β-catenin [13] and Cdc42 [3]. | |
| References: | |
| Secondary Transduction Mechanisms |
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| Transducer | Effector/Response |
| G protein (identity unknown) | |
| References: | |
| Tissue Distribution
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| Expression Datasets |
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| Biologically Significant Variants
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| General Comments |
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ADGRA1 (formerly GPR123) is an orphan receptor that belongs to Family III Adhesion-GPCRs together with ADGRA2 (GPR124) and ADGRA3 (GPR125) [1]. Phylogenetic analysis suggests that ADGRA1-3 share a common ancestor suggesting the evolution from an ancestral gene through gene duplication [1]. Deuterostome invertebrates like ciona, amphioxus, sea urchin and acorn worms contain a single copy that is very similar to ADGRA1-3 [9,12,14] indicating a gene duplication event at the emergence of vertebrates. ADGRA1 does not contain a GPCR proteolysis site (GPS) [7], a domain that facilitates proteolytic cleavage in many Adhesion-GPCRs [11]. Gene prediction [8] of 16 human exons of which only 6 are supported by cDNAs. Rat genomic sequence has a gap of about 104 bases in the last coding exon which, if accounted for, would predict a protein of about 577 amino acids assuming that there are no insertions or deletions relative to the mouse cDNA sequence in the gap. The predicted seqeuence (Protein ID: XP_219468.4) uses a first coding exon not supported by the mouse cDNA, skips the sequencing gap and is in wrong reading frame after the gap. The human mouse and rat proteins all have very short, about 20 residues, amino terminal extracellular domains in contrast to the very large extracellular doamins of most of the class B receptors. |
References
1. 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]
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. Chang J, Mancuso MR, Maier C, Liang X, Yuki K, Yang L, Kwong JW, Wang J, Rao V, Vallon M et al.. (2017) Gpr124 is essential for blood-brain barrier integrity in central nervous system disease. Nat Med, 23 (4): 450-460. [PMID:28288111]
4. Cho C, Smallwood PM, Nathans J. (2017) Reck and Gpr124 Are Essential Receptor Cofactors for Wnt7a/Wnt7b-Specific Signaling in Mammalian CNS Angiogenesis and Blood-Brain Barrier Regulation. Neuron, 95 (5): 1056-1073.e5. [PMID:28803732]
5. Chong ZS, Ohnishi S, Yusa K, Wright GJ. (2018) Pooled extracellular receptor-ligand interaction screening using CRISPR activation. Genome Biol, 19 (1): 205. [PMID:30477585]
6. Eubelen M, Bostaille N, Cabochette P, Gauquier A, Tebabi P, Dumitru AC, Koehler M, Gut P, Alsteens D, Stainier DYR et al.. (2018) A molecular mechanism for Wnt ligand-specific signaling. Science, 361 (6403). [PMID:30026314]
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. 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]
10. Lagerström MC, Rabe N, Haitina T, Kalnina I, Hellström AR, Klovins J, Kullander K, Schiöth HB. (2007) The evolutionary history and tissue mapping of GPR123: specific CNS expression pattern predominantly in thalamic nuclei and regions containing large pyramidal cells. J Neurochem, 100 (4): 1129-42. [PMID:17212699]
11. Lin HH, Chang GW, Davies JQ, Stacey M, Harris J, Gordon S. (2004) Autocatalytic cleavage of the EMR2 receptor occurs at a conserved G protein-coupled receptor proteolytic site motif. J Biol Chem, 279 (30): 31823-32. [PMID:15150276]
12. 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]
13. Posokhova E, Shukla A, Seaman S, Volate S, Hilton MB, Wu B, Morris H, Swing DA, Zhou M, Zudaire E et al.. (2015) GPR124 functions as a WNT7-specific coactivator of canonical β-catenin signaling. Cell Rep, 10 (2): 123-30. [PMID:25558062]
14. 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]
15. Vallon M, Essler M. (2006) Proteolytically processed soluble tumor endothelial marker (TEM) 5 mediates endothelial cell survival during angiogenesis by linking integrin alpha(v)beta3 to glycosaminoglycans. J Biol Chem, 281 (45): 34179-88. [PMID:16982628]
16. Vanhollebeke B, Stone OA, Bostaille N, Cho C, Zhou Y, Maquet E, Gauquier A, Cabochette P, Fukuhara S, Mochizuki N et al.. (2015) Tip cell-specific requirement for an atypical Gpr124- and Reck-dependent Wnt/β-catenin pathway during brain angiogenesis. Elife, 4. [PMID:26051822]
17. 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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