Biology:GPR126

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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]

Disease

Mouse models have shown GPR126 deletion to affect cartilage biology and spinal column development,[23] supporting findings that variants of GPR126 have been associated with adolescent idiopathic scoliosis,[17] and Mutations have been shown to be responsible for severe arthrogryposis multiplex congenita [24]

References

  1. ↑ "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. February 2003. doi:10.1016/S0006-291X(03)00026-3. PMID 12565841. 
  2. ↑ "Entrez Gene: GPR126 G protein-coupled receptor 126". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57211. 
  3. ↑ "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews 67 (2): 338–67. April 2015. doi:10.1124/pr.114.009647. PMID 25713288. 
  4. ↑ Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer. 2011. ISBN 978-1-4419-7912-4. 
  5. ↑ "Sticky signaling--adhesion class G protein-coupled receptors take the stage". Science Signaling 6 (276): re3. May 2013. doi:10.1126/scisignal.2003825. PMID 23695165. 
  6. ↑ "A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis". The EMBO Journal 31 (6): 1364–78. March 2012. doi:10.1038/emboj.2012.26. PMID 22333914. 
  7. ↑ "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews 67 (2): 338–67. Apr 2015. doi:10.1124/pr.114.009647. PMID 25713288. 
  8. ↑ 8.0 8.1 "VIGR--a novel inducible adhesion family G-protein coupled receptor in endothelial cells". FEBS Letters 569 (1–3): 149–55. July 2004. doi:10.1016/j.febslet.2004.05.038. PMID 15225624. 
  9. ↑ "Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126". Science Signaling 7 (338): ra76. August 2014. doi:10.1126/scisignal.2005347. PMID 25118328. 
  10. ↑ 10.0 10.1 "The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211". Neuron 85 (4): 755–69. February 2015. doi:10.1016/j.neuron.2014.12.057. PMID 25695270. 
  11. ↑ 11.0 11.1 "GPR126 protein regulates developmental and pathological angiogenesis through modulation of VEGFR2 receptor signaling". The Journal of Biological Chemistry 289 (50): 34871–85. December 2014. doi:10.1074/jbc.M114.571000. PMID 25217645. 
  12. ↑ "Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation". The Journal of Neuroscience 33 (46): 17976–85. November 2013. doi:10.1523/JNEUROSCI.1809-13.2013. PMID 24227709. 
  13. ↑ "Many sequence variants affecting diversity of adult human height". Nature Genetics 40 (5): 609–15. May 2008. doi:10.1038/ng.122. PMID 18391951. 
  14. ↑ "Identification of ten loci associated with height highlights new biological pathways in human growth". Nature Genetics 40 (5): 584–91. May 2008. doi:10.1038/ng.125. PMID 18391950. 
  15. ↑ "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. April 2009. doi:10.1371/journal.pgen.1000445. PMID 19343178. 
  16. ↑ "Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function". Nature Genetics 42 (1): 45–52. January 2010. doi:10.1038/ng.500. PMID 20010835. 
  17. ↑ 17.0 17.1 "Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis". Nature Genetics 45 (6): 676–9. June 2013. doi:10.1038/ng.2639. PMID 23666238. 
  18. ↑ "A genetic screen identifies genes essential for development of myelinated axons in zebrafish". Developmental Biology 298 (1): 118–31. October 2006. doi:10.1016/j.ydbio.2006.06.021. PMID 16875686. 
  19. ↑ "A G protein-coupled receptor is essential for Schwann cells to initiate myelination". Science 325 (5946): 1402–5. September 2009. doi:10.1126/science.1173474. PMID 19745155. Bibcode: 2009Sci...325.1402M. 
  20. ↑ "The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse". PLOS ONE 5 (11): e14047. November 2010. doi:10.1371/journal.pone.0014047. PMID 21124978. Bibcode: 2010PLoSO...514047W. 
  21. ↑ "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. October 2013. doi:10.1073/pnas.1304837110. PMID 24082093. Bibcode: 2013PNAS..11016898P. 
  22. ↑ "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. November 2013. doi:10.1242/dev.098061. PMID 24067352. 
  23. ↑ "Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice". Human Molecular Genetics 24 (15): 4365–73. August 2015. doi:10.1093/hmg/ddv170. PMID 25954032. 
  24. ↑ "Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita". American Journal of Human Genetics 96 (6): 955–61. June 2015. doi:10.1016/j.ajhg.2015.04.014. PMID 26004201. 

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