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

BMC Research Notes

Gunnar Kleinau²  Heike Biebermann²  Vera Knäuper³  Matthias H Tschöp¹  Annette Grüters²  Timo D Müller¹  Jana Fischer²  Brinja Leinweber²  Anne Müller² 

[1] Institute for Diabetes and Obesity, Helmholtz Center Munich, Munich, Germany, and Division of Metabolic Diseases, Department of Medicine, Technische Universität München, Munich, Germany;Institute of Experimental Pediatric Endocrinology, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Ostring 3, 13353 Berlin, Germany;School of Dentistry College of Biomedical & Life Sciences, Cardiff University, Wales, UK

关键词: Constitutive activation;    Antagonist;    Inverse agonist;    Signaling mechanism;    G-protein coupled receptor 83;   

Others  :  1091947
DOI  :  10.1186/1756-0500-7-913

 received in 2014-10-16, accepted in 2014-12-11,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Müller et al.; licensee BioMed Central.

【 图 表 】

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