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

Muller, Anne, Leinweber, Brinja, Fischer, Jana, Muller, Timo D., Gruters, Annette, Tschop, Matthias H., Knauper, Vera, Biebermann, Heike and Kleinau, Gunnar 2014. The extracellular N-terminal domain of G-protein coupled receptor 83 regulates signaling properties and is an intramolecular inverse agonist. BMC Research Notes 7 , 913. 10.1186/1756-0500-7-913

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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.

Item Type: Article
Date Type: Published Online
Status: Published
Schools: Dentistry
Subjects: Q Science > Q Science (General)
Additional Information: Pdf uploaded in accordance with the publisher’s policy at http://www.sherpa.ac.uk/romeo/issn/1756-0500/ (accessed 22/01/2015)
Publisher: BioMed Central
ISSN: 1756-0500
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 11 December 2014
Last Modified: 28 Feb 2020 09:30
URI: http://orca.cardiff.ac.uk/id/eprint/69392

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