The extracellular N-terminal domain of G-protein coupled receptor 83 regulates signaling properties and is an intramolecular inverse agonist

Anne Müller, Brinja Leinweber, Jana Fischer, Timo D. Müller, Annette Grüters, Matthias H. Tschöp, Vera Knäuper, Heike Biebermann*, Gunnar Kleinau

*Corresponding author for this work
7 Citations (Scopus)

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. Findings: 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.

Original languageEnglish
Article number913
JournalBMC Research Notes
Volume7
Issue number1
DOIs
Publication statusPublished - 01.01.2014

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

Fingerprint

Dive into the research topics of 'The extracellular N-terminal domain of G-protein coupled receptor 83 regulates signaling properties and is an intramolecular inverse agonist'. Together they form a unique fingerprint.

Cite this