The extracellular N-terminal domain of G-protein coupled receptor 83 regulates signaling properties and is an intramolecular inverse agonist
| العنوان: | The extracellular N-terminal domain of G-protein coupled receptor 83 regulates signaling properties and is an intramolecular inverse agonist |
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| المؤلفون: | Annette Grüters, Anne Müller, Jana Fischer, Timo D. Müller, Heike Biebermann, Vera Knäuper, Gunnar Kleinau, Matthias H. Tschöp, Brinja Leinweber |
| المصدر: | BMC Res. Notes 7:913 (2014) BMC Research Notes |
| بيانات النشر: | Springer Science and Business Media LLC, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Models, Molecular, Molecular Sequence Data, Short Report, Biology, Q1, General Biochemistry, Genetics and Molecular Biology, Receptors, G-Protein-Coupled, Mice, GTP-Binding Proteins, Constitutive activation, Extracellular, Enzyme-linked receptor, Animals, Humans, Inverse agonist, Amino Acid Sequence, GABBR2, GABBR1, Receptor, Signaling mechanism, G protein-coupled receptor, Medicine(all), G-protein coupled receptor 83, Binding Sites, Sequence Homology, Amino Acid, Biochemistry, Genetics and Molecular Biology(all), Cell Membrane, Antagonist, General Medicine, Protein Structure, Tertiary, Cell biology, HEK293 Cells, Biochemistry, COS Cells, Mutation, Mitogen-Activated Protein Kinases, Signal transduction, Signal Transduction |
| الوصف: | Background\ud\udRecently, 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.\udFindings\ud\udIn 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.\udConclusions\ud\udFinally, 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. |
| وصف الملف: | application/pdf |
| تدمد: | 1756-0500 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::dfe2753fb0136feea7d2d766e964f645Test https://doi.org/10.1186/1756-0500-7-913Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....dfe2753fb0136feea7d2d766e964f645 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17560500 |
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