title: The extracellular N-terminal domain of G-protein coupled receptor 83 regulates signaling properties and is an intramolecular inverse agonist.
abstract: BACKGROUND
  Recently, the orphan G-protein coupled receptor 83 (GPR83) was identified as a new participant in body weight regulation. This receptor is highly expressed in the hypothalamic arcuate nucleus and is regulated in response to nutrient availability. Gpr83 knock-out mice are protected from diet-induced obesity. Moreover, in a previous study, we designed and characterized several artificial constitutively activating mutations (CAMs) in GPR83. A particular CAM was located in the extracellular N-terminal domain (eNDo) that is highly conserved among GPR83 orthologs. This suggests the contribution of this receptor part into regulation of signaling, which needed a more detailed investigation.
  
  
  RESULTS
  In this present study, therefore, we further explored the role of the eNDo in regulating GPR83-signaling and demonstrate a proof-of-principle approach in that deletion mutants are characterized by a strong increase in basal Gq/11-mediated signaling, whilst none of the additionally characterized signaling pathways (Gs, Gi, G12/13) were activated by the N-terminal deletion variants. Of note, we detected basal GPR83 MAPK-activity of the wild type receptor, which was not increased in the deletion variants.
  
  
  CONCLUSIONS
  Finally, the extracellular portion of GPR83 has a strong regulatory function on this receptor. A suppressive - inverse agonistic - effect of the eNDo on GPR83 signaling activity is demonstrated here, which also suggests a putative link between extracellular receptor activation and proteolytic cleavage. These new insights highlight important aspects of GPR83-regulation and might open options in the development of tools to modulate GPR83-signaling.
authors.forename: Anne
authors.initials: A
authors.lastname: Müller
authors.forename: Brinja
authors.initials: B
authors.lastname: Leinweber
authors.forename: Jana
authors.initials: J
authors.lastname: Fischer
authors.forename: Timo D
authors.initials: TD
authors.lastname: Müller
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Vera
authors.initials: V
authors.lastname: Knäuper
authors.affiliation: Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Ostring 3, 13353 Berlin, Germany. heike.biebermann@charite.de.
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Gunnar
authors.initials: G
authors.lastname: Kleinau
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: C501984:Gpr83 protein, mouse; D043562:Receptors, G-Protein-Coupled; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins