title: Type IV collagen is an activating ligand for the adhesion G protein-coupled receptor GPR126.
abstract: GPR126 is an orphan heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor (GPCR) that is essential for the development of diverse organs. We found that type IV collagen, a major constituent of the basement membrane, binds to Gpr126 and activates its signaling function. Type IV collagen stimulated the production of cyclic adenosine monophosphate in rodent Schwann cells, which require Gpr126 activity to differentiate, and in human embryonic kidney (HEK) 293 cells expressing exogenous Gpr126. Type IV collagen specifically bound to the extracellular amino-terminal region of Gpr126 containing the CUB (complement, Uegf, Bmp1) and pentraxin domains. Gpr126 derivatives lacking the entire amino-terminal region were constitutively active, suggesting that this region inhibits signaling and that ligand binding relieves this inhibition to stimulate receptor activity. A new zebrafish mutation that truncates Gpr126 after the CUB and pentraxin domains disrupted development of peripheral nerves and the inner ear. Thus, our findings identify type IV collagen as an activating ligand for GPR126, define its mechanism of activation, and highlight a previously unrecognized signaling function of type IV collagen in basement membranes.
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Paavola
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Harwin
authors.initials: H
authors.lastname: Sidik
authors.affiliation: Department of Neurobiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: J Bradley
authors.initials: JB
authors.lastname: Zuchero
authors.affiliation: Protein and Nucleic Acid Facility, Stanford University School of Medicine, Stanford, CA 94035, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Eckart
authors.affiliation: Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. wtalbot@stanford.edu.
authors.forename: William S
authors.initials: WS
authors.lastname: Talbot
mesh_terms: D000818:Animals; D019921:Biotinylation; D002448:Cell Adhesion / Q000502:physiology*; D003001:Cloning, Molecular; D024141:Collagen Type IV / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D007758:Ear, Inner / Q000196:embryology*; D040461:Gene Components; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012583:Schwann Cells / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D015027:Zebrafish
chemical_list: C488660:ADGRG6 protein, human; D024141:Collagen Type IV; D017931:DNA Primers; D043562:Receptors, G-Protein-Coupled; D000242:Cyclic AMP