GPR126

Adhesion G protein-coupled receptor G6
Identifiers
Symbols ADGRG6 ; APG1; DREG; GPR126; PS1TP2; VIGR
External IDs OMIM: 612243 MGI: 1916151 HomoloGene: 10724 IUPHAR: GeneCards: ADGRG6 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 57211 215798
Ensembl ENSG00000112414 ENSMUSG00000039116
UniProt Q86SQ4 Q6F3F9
RefSeq (mRNA) NM_001032394 NM_001002268
RefSeq (protein) NP_001027566 NP_001002268
Location (UCSC) Chr 6:
142.3 – 142.45 Mb		 Chr 10:
14.4 – 14.55 Mb
PubMed search

G protein-coupled receptor 126 also known as VIGR and DREG is a protein encoded by the ADGRG6 gene.[1][2][3] GPR126 is a member of the adhesion GPCR family.[4][5] Adhesion GPCRs are characterized by an extended extracellular region often possessing N-terminal protein modules that is linked to a TM7 region via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.[6]

GPR126 is all widely expressed on stromal cells.[7] The N-terminal fragment of GPR126 contains C1r-C1s, Uegf and Bmp1 (CUB), and PTX-like modules.[8]

Ligand

GPR126 was shown to bind collagen IV and laminin-211 promoting cyclic adenosine monophosphate (cAMP) to mediate myelination.[9][10]

Signaling

Upon lipopolysaccharide (LPS) or thrombin stimulation, expression of GPR126 is induced by MAP kinases in endothelial cells.[8] During angiogenesis, GPR126 promotes protein kinase A (PKA)–cAMP-activated signaling in endothelial cells.[11] Forced GPR126 expression in COS-7 cells enhances cAMP levels by coupling to heterotrimeric Gαs/i proteins.[12]

Function

GPR126 has been identified in genomic regions associated with adult height, more specially trunk height,[13][14][15] pulmonary function[16] and adolescent idiopathic scoliosis.[17] In the vertebrate nervous system, many axons are surrounded by a myelin sheath to conduct action potentials rapidly and efficiently. Applying a genetic screen in zebrafish mutants, Talbot’s group demonstrated that GPR126 affects the development of myelinated axons.[18] GPR126 drives the differentiation of Schwann cells through inducing cAMP levels, which causes Oct6 transcriptional activities to promote myelin gene activity.[19] Mutation of gpr126 in zebrafish affects peripheral myelination. Monk’s group demonstrated domain-specific functions of GPR126 during Schwann cells development: the NTF is necessary and sufficient for axon sorting, while the CTF promotes wrapping through cAMP induction to regulate early and late stages of Schwann cells development.[10]

Outside of neurons, GPR126 function is required for heart and inner ear development.[20][21][22] GPR126 stimulates VEGF signaling and angiogenesis by modulating VEGF receptor 2 (VEGFR2) expression through STAT5 and GATA2 in endothelial cells.[11]

References

  1. ↑ Fredriksson R, Gloriam DE, Höglund PJ, Lagerström MC, Schiöth HB (Feb 2003). "There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini". Biochemical and Biophysical Research Communications 301 (3): 725–34. doi:10.1016/S0006-291X(03)00026-3. PMID 12565841.
  2. ↑ "Entrez Gene: GPR126 G protein-coupled receptor 126".
  3. ↑ Hamann, J; Aust, G; Araç, D; Engel, FB; Formstone, C; Fredriksson, R; Hall, RA; Harty, BL; Kirchhoff, C; Knapp, B; Krishnan, A; Liebscher, I; Lin, HH; Martinelli, DC; Monk, KR; Peeters, MC; Piao, X; Prömel, S; Schöneberg, T; Schwartz, TW; Singer, K; Stacey, M; Ushkaryov, YA; Vallon, M; Wolfrum, U; Wright, MW; Xu, L; Langenhan, T; Schiöth, HB (April 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors.". Pharmacological reviews 67 (2): 338–67. doi:10.1124/pr.114.009647. PMID 25713288.
  4. ↑ Stacey M, Yona S (2011). Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. ISBN 1-4419-7912-3.
  5. ↑ Langenhan, T; Aust, G; Hamann, J (21 May 2013). "Sticky signaling--adhesion class G protein-coupled receptors take the stage.". Science signaling 6 (276): re3. doi:10.1126/scisignal.2003825. PMID 23695165.
  6. ↑ Araç D, Boucard AA, Bolliger MF, Nguyen J, Soltis SM, Südhof TC, Brunger AT (Mar 2012). "A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis". The EMBO Journal 31 (6): 1364–78. doi:10.1038/emboj.2012.26. PMC 3321182. PMID 22333914.
  7. ↑ Hamann J, Aust G, Araç D, Engel FB, Formstone C, Fredriksson R, Hall RA, Harty BL, Kirchhoff C, Knapp B, Krishnan A, Liebscher I, Lin HH, Martinelli DC, Monk KR, Peeters MC, Piao X, Prömel S, Schöneberg T, Schwartz TW, Singer K, Stacey M, Ushkaryov YA, Vallon M, Wolfrum U, Wright MW, Xu L, Langenhan T, Schiöth HB (Apr 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews 67 (2): 338–67. doi:10.1124/pr.114.009647. PMID 25713288.
  8. 1 2 Stehlik C, Kroismayr R, Dorfleutner A, Binder BR, Lipp J (Jul 2004). "VIGR--a novel inducible adhesion family G-protein coupled receptor in endothelial cells". FEBS Letters 569 (1-3): 149–55. doi:10.1016/j.febslet.2004.05.038. PMID 15225624.
  9. ↑ Paavola KJ, Sidik H, Zuchero JB, Eckart M, Talbot WS (Aug 2014). "Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126". Science Signaling 7 (338): ra76. doi:10.1126/scisignal.2005347. PMID 25118328.
  10. 1 2 Petersen SC, Luo R, Liebscher I, Giera S, Jeong SJ, Mogha A, Ghidinelli M, Feltri ML, Schöneberg T, Piao X, Monk KR (Feb 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. doi:10.1016/j.neuron.2014.12.057. PMID 25695270.
  11. 1 2 Cui H, Wang Y, Huang H, Yu W, Bai M, Zhang L, Bryan BA, Wang Y, Luo J, Li D, Ma Y, Liu M (Dec 2014). "GPR126 protein regulates developmental and pathological angiogenesis through modulation of VEGFR2 receptor signaling". The Journal of Biological Chemistry 289 (50): 34871–85. doi:10.1074/jbc.M114.571000. PMID 25217645.
  12. ↑ Mogha A, Benesh AE, Patra C, Engel FB, Schöneberg T, Liebscher I, Monk KR (Nov 2013). "Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation". The Journal of Neuroscience 33 (46): 17976–85. doi:10.1523/JNEUROSCI.1809-13.2013. PMID 24227709.
  13. ↑ Gudbjartsson DF, Walters GB, Thorleifsson G, Stefansson H, Halldorsson BV, Zusmanovich P, Sulem P, Thorlacius S, Gylfason A, Steinberg S, Helgadottir A, Ingason A, Steinthorsdottir V, Olafsdottir EJ, Olafsdottir GH, Jonsson T, Borch-Johnsen K, Hansen T, Andersen G, Jorgensen T, Pedersen O, Aben KK, Witjes JA, Swinkels DW, den Heijer M, Franke B, Verbeek AL, Becker DM, Yanek LR, Becker LC, Tryggvadottir L, Rafnar T, Gulcher J, Kiemeney LA, Kong A, Thorsteinsdottir U, Stefansson K (May 2008). "Many sequence variants affecting diversity of adult human height". Nature Genetics 40 (5): 609–15. doi:10.1038/ng.122. PMID 18391951.
  14. ↑ Lettre G, Jackson AU, Gieger C, Schumacher FR, Berndt SI, Sanna S, Eyheramendy S, Voight BF, Butler JL, Guiducci C, Illig T, Hackett R, Heid IM, Jacobs KB, Lyssenko V, Uda M, Boehnke M, Chanock SJ, Groop LC, Hu FB, Isomaa B, Kraft P, Peltonen L, Salomaa V, Schlessinger D, Hunter DJ, Hayes RB, Abecasis GR, Wichmann HE, Mohlke KL, Hirschhorn JN (May 2008). "Identification of ten loci associated with height highlights new biological pathways in human growth". Nature Genetics 40 (5): 584–91. doi:10.1038/ng.125. PMID 18391950.
  15. ↑ Soranzo N, Rivadeneira F, Chinappen-Horsley U, Malkina I, Richards JB, Hammond N, Stolk L, Nica A, Inouye M, Hofman A, Stephens J, Wheeler E, Arp P, Gwilliam R, Jhamai PM, Potter S, Chaney A, Ghori MJ, Ravindrarajah R, Ermakov S, Estrada K, Pols HA, Williams FM, McArdle WL, van Meurs JB, Loos RJ, Dermitzakis ET, Ahmadi KR, Hart DJ, Ouwehand WH, Wareham NJ, Barroso I, Sandhu MS, Strachan DP, Livshits G, Spector TD, Uitterlinden AG, Deloukas P (Apr 2009). "Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size". PLoS Genetics 5 (4): e1000445. doi:10.1371/journal.pgen.1000445. PMC 2661236. PMID 19343178.
  16. ↑ Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, Franceschini N, van Durme YM, Chen TH, Barr RG, Schabath MB, Couper DJ, Brusselle GG, Psaty BM, van Duijn CM, Rotter JI, Uitterlinden AG, Hofman A, Punjabi NM, Rivadeneira F, Morrison AC, Enright PL, North KE, Heckbert SR, Lumley T, Stricker BH, O'Connor GT, London SJ (Jan 2010). "Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function". Nature Genetics 42 (1): 45–52. doi:10.1038/ng.500. PMC 2832852. PMID 20010835.
  17. ↑ Kou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, Qiu X, Sharma S, Takimoto A, Ogura Y, Jiang H, Yan H, Kono K, Kawakami N, Uno K, Ito M, Minami S, Yanagida H, Taneichi H, Hosono N, Tsuji T, Suzuki T, Sudo H, Kotani T, Yonezawa I, Londono D, Gordon D, Herring JA, Watanabe K, Chiba K, Kamatani N, Jiang Q, Hiraki Y, Kubo M, Toyama Y, Tsunoda T, Wise CA, Qiu Y, Shukunami C, Matsumoto M, Ikegawa S (Jun 2013). "Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis". Nature Genetics 45 (6): 676–9. doi:10.1038/ng.2639. PMID 23666238.
  18. ↑ Pogoda HM, Sternheim N, Lyons DA, Diamond B, Hawkins TA, Woods IG, Bhatt DH, Franzini-Armstrong C, Dominguez C, Arana N, Jacobs J, Nix R, Fetcho JR, Talbot WS (Oct 2006). "A genetic screen identifies genes essential for development of myelinated axons in zebrafish". Developmental Biology 298 (1): 118–31. doi:10.1016/j.ydbio.2006.06.021. PMID 16875686.
  19. ↑ Monk KR, Naylor SG, Glenn TD, Mercurio S, Perlin JR, Dominguez C, Moens CB, Talbot WS (Sep 2009). "A G protein-coupled receptor is essential for Schwann cells to initiate myelination". Science 325 (5946): 1402–5. doi:10.1126/science.1173474. PMID 19745155.
  20. ↑ Waller-Evans H, Prömel S, Langenhan T, Dixon J, Zahn D, Colledge WH, Doran J, Carlton MB, Davies B, Aparicio SA, Grosse J, Russ AP (18 November 2010). "The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse". PLOS ONE 5 (11): e14047. doi:10.1371/journal.pone.0014047. PMID 21124978.
  21. ↑ Patra C, van Amerongen MJ, Ghosh S, Ricciardi F, Sajjad A, Novoyatleva T, Mogha A, Monk KR, Mühlfeld C, Engel FB (Oct 2013). "Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent". Proceedings of the National Academy of Sciences of the United States of America 110 (42): 16898–903. doi:10.1073/pnas.1304837110. PMID 24082093.
  22. ↑ Geng FS, Abbas L, Baxendale S, Holdsworth CJ, Swanson AG, Slanchev K, Hammerschmidt M, Topczewski J, Whitfield TT (Nov 2013). "Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene". Development 140 (21): 4362–74. doi:10.1242/dev.098061. PMID 24067352.

External links

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