G protein-coupled receptor 126 also known asVIGR andDREG is aprotein encoded by theADGRG6gene.[5][6][7] GPR126 is a member of theadhesion GPCR family.[8][9]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.[10]
GPR126 is all widely expressed on stromal cells.[11] The N-terminal fragment of GPR126 contains C1r-C1s, Uegf and Bmp1 (CUB), and PTX-like modules.[12]
Upon lipopolysaccharide (LPS) or thrombin stimulation, expression of GPR126 is induced by MAP kinases in endothelial cells.[12] During angiogenesis, GPR126 promotes protein kinase A (PKA)–cAMP-activated signaling in endothelial cells.[15] Forced GPR126 expression in COS-7 cells enhances cAMP levels by coupling to heterotrimeric Gαs/i proteins.[16]
GPR126 has been identified in genomic regions associated with adult height, more specially trunk height,[17][18][19] pulmonary function[20] and adolescent idiopathic scoliosis.[21] 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.[22] GPR126 drives the differentiation of Schwann cells through inducing cAMP levels, which causes Oct6 transcriptional activities to promote myelin gene activity.[23] Mutation ofgpr126 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.[14]
Outside of neurons, GPR126 function is required for heart and inner ear development.[24][25][26] GPR126 stimulates VEGF signaling and angiogenesis by modulating VEGF receptor 2 (VEGFR2) expression through STAT5 and GATA2 in endothelial cells.[15]
Mouse models have shown GPR126 deletion to affect cartilage biology and spinal column development,[27] supporting findings that variants of GPR126 have been associated with adolescent idiopathicscoliosis,[21] and Mutations have been shown to be responsible for severearthrogryposis multiplex congenita[28]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Fredriksson R, Gloriam DE, Höglund PJ, Lagerström MC, Schiöth HB (February 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.PMID12565841.
^Stacey M, Yona S (2011).Adhesion-GPCRs: Structure to Function (Advances in Experimental Medicine and Biology). Berlin: Springer.ISBN978-1-4419-7912-4.
^abKou I, Takahashi Y, Johnson TA, Takahashi A, Guo L, Dai J, et al. (June 2013). "Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis".Nature Genetics.45 (6):676–9.doi:10.1038/ng.2639.PMID23666238.S2CID205347099.
