ADGRA1 | Adhesion Class GPCRs | IUPHAR/BPS Guide to PHARMACOLOGY

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ADGRA1

Target not currently curated in GtoImmuPdb

Target id: 197

Nomenclature: ADGRA1

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 7 560 10q26 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
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
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 include ADGRG1 [8], 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 [7] for other adhesion GPCRs to transduce signal through G proteins.
References: 
Secondary Transduction Mechanisms
Transducer Effector/Response
G protein (identity unknown)
References: 
Tissue Distribution
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

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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
Type:  Splice variant
Species:  Human
Description:  The physiological effect of this variant is unknown.
Amino acids:  464
Nucleotide accession: 
Protein accession: 
References:  3
General Comments
ADGRA1 (formerly GPR123) is an orphan receptor that belongs to Family III Adhesion-GPCRs together with ADGRA2 (GPR124) and ADGRA3 (GPR125) [2]. 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 [9,13,15] indicating a gene duplication event at the emergence of vertebrates. ADGRA1 does not contain a GPCR proteolysis site (GPS) [5], a domain that facilitates proteolytic cleavage in many Adhesion-GPCRs [11].

Gene prediction [6] 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. 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. 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]

7. 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]

8. 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]

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. 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. 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]

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