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ADGRG6

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Target id: 200

Nomenclature: ADGRG6

Family: Adhesion Class GPCRs

This receptor has a proposed ligand; see the Latest Pairings page for more information.

Contents:

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 1221 6q24.2 ADGRG6 adhesion G protein-coupled receptor G6 18,23
Mouse 7 1165 10 A2 Adgrg6 adhesion G protein-coupled receptor G6
Rat 7 1217 1p13 Adgrg6 adhesion G protein-coupled receptor G6
Previous and Unofficial Names Click here for help
developmentally regulated GPCR | DREG | GPR126 (G protein-coupled receptor 126) | vascular inducible GPCR | VIGR
Database Links Click here for help
Specialist databases
GPCRdb gp126_human (Hs), gp126_mouse (Mm)
Other databases
Alphafold Q86SQ4 (Hs), Q6F3F9 (Mm)
CATH/Gene3D 2.60.120.290
ChEMBL Target CHEMBL4523884 (Hs)
Ensembl Gene ENSG00000112414 (Hs), ENSMUSG00000039116 (Mm), ENSRNOG00000011411 (Rn)
Entrez Gene 57211 (Hs), 215798 (Mm), 308376 (Rn)
Human Protein Atlas ENSG00000112414 (Hs)
KEGG Gene hsa:57211 (Hs), mmu:215798 (Mm), rno:308376 (Rn)
OMIM 12243 (Hs)
Pharos Q86SQ4 (Hs)
RefSeq Nucleotide NM_001032394 (Hs), NM_020455 (Hs), NM_001032395 (Hs), NM_198569 (Hs), NM_001002268 (Mm)
RefSeq Protein NP_001027567 (Hs), NP_001027566 (Hs), NP_940971 (Hs), NP_065188 (Hs), NP_001002268 (Mm)
UniProtKB Q86SQ4 (Hs), Q6F3F9 (Mm)
Wikipedia ADGRG6 (Hs)
Endogenous agonists
Peptides derived from the Stachel sequence: THFGVLMDLPRSASQL; Progesterone and 17-hydroxyprogesterone seem to activate Gi signaling via GPR126 (ADGRG6).  [1,12]
Agonist Comments
Type IV collagen has been shown to bind to ADGRG6 and activate the signalling function of the receptor [19]. Peptides derived from the Stachel sequence, THFGVLMDLPRSASQL [12], and apomorphine hydrochloride have agonist activity [4].
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family
References:  12,15,21
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
References:  21
Tissue Distribution Click here for help
Transcripts of approximately 7.7 and 4.7kb in placenta and to a lower extent in pancreas and liver and maybe brain. Not detected in lung, skeletal muscle or kidney.
Species:  Human
Technique:  Northern blotting.
References:  23
Placenta, liver, testis, muscle, pancreas, uterus and primary human endothelial cells (HUVEC)
Species:  Human
Technique:  Northern blot and EST
References:  2-3,23
Primary human Schwann cells
Species:  Human
Technique:  Microarray analysis
References:  14
Bergmann glia
Species:  Mouse
Technique:  RT-PCR and single cell RT-PCR
References:  9
Lung, spleen, 11-, 15- and 17-day embryo > 7-day embryo, heart, brain, skeletal muscle, kidney, testis. Not detected in liver.
Species:  Mouse
Technique:  RT-PCR.
References:  18
P4 mouse sciatic nerve (Schwann cells, robust expression), embryonic dorsal root ganglia neurons (very weak)
Species:  Mouse
Technique:  RT-PCR
References:  17
Embryonic somite, trophoblast giant cells and heart
Species:  Mouse
Technique:  LacZ insertion
References:  25
Spleen, lung, embryonic presomitic mesoderm (E9), somites (E10/E11) and heart (E10/E11)
Species:  Mouse
Technique:  RT-PCR, in situ hybridisation and EST
References:  6,18
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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Functional Assays Click here for help
ADGRG6 couples to Gs protein.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  Change in proximity luminescence by AlphaScreen assay.
References:  12,21
Physiological Functions Click here for help
Schwann cell myelination in mouse
Species:  Mouse
Tissue:  Peripheral sensory nerve, motor nerve, sciatic nerve
References:  17
Peripheral nerve development
Species:  Mouse
Tissue:  Sciatic nerve
References:  17
Embryonic development (embryos die of cardiac defects)
Species:  Mouse
Tissue: 
References:  25
Physiological Consequences of Altering Gene Expression Click here for help
Fully penetrant embryonic lethality, cardiac defects. Technique: lacZ insertional knockout; 7TM targeted
Species:  Mouse
Tissue:  Full-body knockout, embryo examined
Technique:  Gene knockouts
References:  25
Some embryonic lethality, absent myelination, nerve development defects
Species:  Mouse
Tissue:  Full-body knockout, nerves examined
Technique:  Knockout; C1r-C1s/Uegf/Bmp1 (CUB) and pentraxin (PTX)-like modules targeted
References:  17
Adgrg6 is mechano-sensitive and essential for normal differentiation of promyelinating Schwann cells and for normal myelination of axons and for proper heart development. Further, conditional deletion of Adgrg6 revealed that this adhesion GPCR is involved in regulation of body length and bone mass and intervertebral disc function.
Species:  Mouse
Tissue: 
Technique: 
References:  13,15-17,20-21,24-25
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Adolescent idiopathic scoliosis
Role:  A SNP (rs6570507) associated with adolescent idiopathic scoliosis was found in ADGRG6
References:  10
Disease:  Arthrogryposis multiplex congenita
Synonyms: lethal congenital contracture syndrome-9
OMIM: 616503
References:  22
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Description:  Variation in pulmonary function
SNP accession:  rs3817928
References:  7
Type:  Splice variants
Species:  Human
Description:  Four splice variants were described with all possible combinations of including or excluding exons 6 and 25.
References:  18
Type:  Single nucleotide polymorphism
Species:  Human
Description:  Variation in height (phenotype MIM number: 606255)
Amino acid change:  142703877G>A
SNP accession:  rs4896582
References:  11
General Comments
ADGRG6 (fromerly GPR126) is an orphan receptor belonging to Family VIII Adhesion-GPCRs together with ADGRG1-5 and ADGRG7 [5]. The N terminus of ADGRG6 contains a GPCR proteolysis site (GPS), a CUB domain and a pentraxin (PTX) domain. There are numerous transcript variants, some lead to changes in the N terminus’ domain structure [8]. Laminin-211 interacts with ADGRG6 [21].

Addition of forskolin can rescue mutant phenotype in zebrafish [16], though direct evidence of Gs coupling/adenylate cyclase stimulation has not been shown.

References

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1. An W, Lin H, Ma L, Zhang C, Zheng Y, Cheng Q, Ma C, Wu X, Zhang Z, Zhong Y et al.. (2022) Progesterone activates GPR126 to promote breast cancer development via the Gi pathway. Proc Natl Acad Sci U S A, 119 (15): e2117004119. [PMID:35394864]

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. Bradley EC, Cunningham RL, Wilde C, Morgan RK, Klug EA, Letcher SM, Schöneberg T, Monk KR, Liebscher I, Petersen SC. (2019) In vivo identification of small molecules mediating Gpr126/Adgrg6 signaling during Schwann cell development. Ann N Y Acad Sci, 1456 (1): 44-63. [PMID:31529518]

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. Haitina T, Olsson F, Stephansson O, Alsiö J, Roman E, Ebendal T, Schiöth HB, Fredriksson R. (2008) Expression profile of the entire family of Adhesion G protein-coupled receptors in mouse and rat. BMC Neurosci, 9: 43. [PMID:18445277]

7. Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, Franceschini N, van Durme YM, Chen TH, Barr RG et al.. (2010) Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet, 42 (1): 45-52. [PMID:20010835]

8. Knierim AB, Röthe J, Çakir MV, Lede V, Wilde C, Liebscher I, Thor D, Schöneberg T. (2019) Genetic basis of functional variability in adhesion G protein-coupled receptors. Sci Rep, 9 (1): 11036. [PMID:31363148]

9. Koirala S, Corfas G. (2010) Identification of novel glial genes by single-cell transcriptional profiling of Bergmann glial cells from mouse cerebellum. PLoS ONE, 5 (2): e9198. [PMID:20169146]

10. Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, Qiu X, Sharma S, Takimoto A, Ogura Y et al.. (2013) Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet, 45 (6): 676-679. [PMID:23666238]

11. Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, Eyheramendy S, Voight BF, Butler JL, Guiducci C et al.. (2008) Identification of ten loci associated with height highlights new biological pathways in human growth. Nat Genet, 40 (5): 584-91. [PMID:18391950]

12. Liebscher I, Schön J, Petersen SC, Fischer L, Auerbach N, Demberg LM, Mogha A, Cöster M, Simon KU, Rothemund S et al.. (2014) A tethered agonist within the ectodomain activates the adhesion G protein-coupled receptors GPR126 and GPR133. Cell Rep, 9 (6): 2018-26. [PMID:25533341]

13. Liu Z, Easson GWD, Zhao J, Makki N, Ahituv N, Hilton MJ, Tang SY, Gray RS. (2019) Dysregulation of STAT3 signaling is associated with endplate-oriented herniations of the intervertebral disc in Adgrg6 mutant mice. PLoS Genet, 15 (10): e1008096. [PMID:31652254]

14. Miller SJ, Jessen WJ, Mehta T, Hardiman A, Sites E, Kaiser S, Jegga AG, Li H, Upadhyaya M, Giovannini M et al.. (2009) Integrative genomic analyses of neurofibromatosis tumours identify SOX9 as a biomarker and survival gene. EMBO Mol Med, 1 (4): 236-48. [PMID:20049725]

15. Mogha A, Benesh AE, Patra C, Engel FB, Schöneberg T, Liebscher I, Monk KR. (2013) Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation. J Neurosci, 33 (46): 17976-85. [PMID:24227709]

16. 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]

17. Monk KR, Oshima K, Jörs S, Heller S, Talbot WS. (2011) Gpr126 is essential for peripheral nerve development and myelination in mammals. Development, 138 (13): 2673-80. [PMID:21613327]

18. Moriguchi T, Haraguchi K, Ueda N, Okada M, Furuya T, Akiyama T. (2004) DREG, a developmentally regulated G protein-coupled receptor containing two conserved proteolytic cleavage sites. Genes Cells, 9 (6): 549-60. [PMID:15189448]

19. Paavola KJ, Sidik H, Zuchero JB, Eckart M, Talbot WS. (2014) Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126. Sci Signal, 7 (338): ra76. [PMID:25118328]

20. Patra C, van Amerongen MJ, Ghosh S, Ricciardi F, Sajjad A, Novoyatleva T, Mogha A, Monk KR, Mühlfeld C, Engel FB. (2013) Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent. Proc Natl Acad Sci USA, 110 (42): 16898-903. [PMID:24082093]

21. Petersen SC, Luo R, Liebscher I, Giera S, Jeong SJ, Mogha A, Ghidinelli M, Feltri ML, Schöneberg T, Piao X et al.. (2015) The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211. Neuron, 85 (4): 755-69. [PMID:25695270]

22. Ravenscroft G, Nolent F, Rajagopalan S, Meireles AM, Paavola KJ, Gaillard D, Alanio E, Buckland M, Arbuckle S, Krivanek M et al.. (2015) Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita. Am J Hum Genet, 96 (6): 955-61. [PMID:26004201]

23. Stehlik C, Kroismayr R, Dorfleutner A, Binder BR, Lipp J. (2004) VIGR--a novel inducible adhesion family G-protein coupled receptor in endothelial cells. FEBS Lett, 569 (1-3): 149-55. [PMID:15225624]

24. Sun P, He L, Jia K, Yue Z, Li S, Jin Y, Li Z, Siwko S, Xue F, Su J et al.. (2020) Regulation of body length and bone mass by Gpr126/Adgrg6. Sci Adv, 6 (12): eaaz0368. [PMID:32219165]

25. Waller-Evans H, Prömel S, Langenhan T, Dixon J, Zahn D, Colledge WH, Doran J, Carlton MB, Davies B, Aparicio SA et al.. (2010) The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse. PLoS ONE, 5 (11): e14047. [PMID:21124978]

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