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ADGRA1

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Target not currently curated in GtoImmuPdb

Target id: 197

Nomenclature: ADGRA1

Family: Adhesion Class GPCRs

Gene and Protein Information Click here for help
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 Click here for help
GPR123 (G protein-coupled receptor 123)
Database Links Click here for help
Specialist databases
GPCRDB agra1_human (Hs)
Other databases
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
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 Click here for help
Transducer Effector/Response
G protein (identity unknown)
Comments:  Principal transduction via dishevelled [6], β-catenin [13] and Cdc42 [3].
References: 
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
G protein (identity unknown)
References: 
Tissue Distribution Click here for help
CNS: cerebral cortex layers 5 and 6, pyramidal cell layers, hippocampus, subiculum, hypothalamus (ventromedial hypothalamic nuclei, dorsomedial), thalamus, medulla (inferior olive) and spinal cord. Low expression in eye, adrenal, liver, uterus, adipose tissue, kidney, ovary, heart and thymus. No expression in skeletal muscle, intestine, lung, testis and epididymis
Species:  Mouse
Technique:  in situ hybridisation and RT-PCR
References:  10
Primarily brain and spinal cord. Lower levels in eye, adrenal, liver. Low levels in uterus, adipose tissue, kidney, ovary, heart, thymus. None observed in skeletal muscle, intestine, lung, spleen, epididymus.
Species:  Rat
Technique:  RT-PCR.
References:  10
Expression Datasets Click here for help

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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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Biologically Significant Variants Click here for help
Type:  Splice variant
Species:  Human
Description:  The physiological effect of this variant is unknown.
Amino acids:  464
Nucleotide accession: 
Protein accession: 
References:  2
General Comments
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

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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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