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BMC Res Notes. 2014 Dec 16;7:913. doi: 10.1186/1756-0500-7-913.

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

Author information

1
Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Ostring 3, 13353 Berlin, Germany. heike.biebermann@charite.de.

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.

PMID:
25516095
PMCID:
PMC4300838
DOI:
10.1186/1756-0500-7-913
[Indexed for MEDLINE]
Free PMC Article

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