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 ORCID: https://orcid.org/0000-0002-3965-9924, 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:	23 May 2023 16:44
URI:	https://orca.cardiff.ac.uk/id/eprint/69392

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