GPR126

Ligand

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

Signaling

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

Function

GPR126 has been identified in genomic regions associated with adult height, more specially trunk height, pulmonary function and adolescent idiopathic scoliosis. 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. GPR126 drives the differentiation of Schwann cells through inducing cAMP levels, which causes Oct6 transcriptional activities to promote myelin gene activity. 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.

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

Disease

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

References

References

1. (February 2003). "There exist at least 30 human G-protein-coupled receptors with long Ser/Thr-rich N-termini". Biochemical and Biophysical Research Communications.
2. "Entrez Gene: GPR126 G protein-coupled receptor 126".
3. (April 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews.
4. (2011). "Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology)". Springer.
5. (May 2013). "Sticky signaling--adhesion class G protein-coupled receptors take the stage". Science Signaling.
6. (March 2012). "A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis". The EMBO Journal.
7. (Apr 2015). "International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G protein-coupled receptors". Pharmacological Reviews.
8. (July 2004). "VIGR--a novel inducible adhesion family G-protein coupled receptor in endothelial cells". FEBS Letters.
9. (August 2014). "Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126". Science Signaling.
10. (February 2015). "The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211". Neuron.
11. (December 2014). "GPR126 protein regulates developmental and pathological angiogenesis through modulation of VEGFR2 receptor signaling". The Journal of Biological Chemistry.
12. (November 2013). "Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation". The Journal of Neuroscience.
13. (May 2008). "Many sequence variants affecting diversity of adult human height". Nature Genetics.
14. (May 2008). "Identification of ten loci associated with height highlights new biological pathways in human growth". Nature Genetics.
15. (April 2009). "Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size". PLOS Genetics.
16. (January 2010). "Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function". Nature Genetics.
17. (June 2013). "Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis". Nature Genetics.
18. (October 2006). "A genetic screen identifies genes essential for development of myelinated axons in zebrafish". Developmental Biology.
19. (September 2009). "A G protein-coupled receptor is essential for Schwann cells to initiate myelination". Science.
20. (November 2010). "The orphan adhesion-GPCR GPR126 is required for embryonic development in the mouse". PLOS ONE.
21. (October 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.
22. (November 2013). "Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene". Development.
23. (August 2015). "Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice". Human Molecular Genetics.
24. (June 2015). "Mutations of GPR126 are responsible for severe arthrogryposis multiplex congenita". American Journal of Human Genetics.