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Title
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Mas-related G protein-coupled receptors : activations, interactions, and their role in inflammation
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Author
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Abstract
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| The largest family of membrane receptors, known as G protein-coupled receptors (GPCRs), are essential to cellular signaling and regulate physiological processes. Presently, ~35%–40% of US FDA-approved medications target GPCRs. A subfamily of GPCRs, Mas-related G protein-coupled receptors (MRGPRs), which belong to the δ-group of the rhodopsin-like GPCRs, was discovered two decades ago. MRGPRs are expressed by small non-myelinated sensory neurons of the dorsal root ganglia and trigeminal ganglia, mast cells, neutrophils, and macrophages and are known to play a role in itch, pain, and pseudo-allergic drug reactions. Moreover, MRGPRs have been identified as mediators in the renin-angiotensin system and cardiovascular biology. In addition, literature suggests that MRGPRs are also involved in inflammatory processes. Despite the fact that humans express eight MRGPRs (MRGPRD to G and X1-X4), information about their activation, signaling pathways, and role in inflammation is insufficient, and most of them are still classified as orphans. Since MRGPRs are involved in itch, pain, and inflammation, which are important physiological processes, the goal of this PhD was to: i) examine the role of MRGPRs in inflammation biology; ii) decipher the activation mechanism of MRGPRs; and iii) elucidate the oligomeric interaction of MRGPRs. Firstly, it was investigated whether β-alanine or alamandine-activated MRGPRD induces interleukin-6 (IL-6) release. It was observed that β-alanine activated MRGPRD-induced IL-6 release via the Gαq/Phospholipase C/NF-kB signaling pathway. Moreover, using IL-6 as a marker for MRGPRD activation, the mechanosensitivity of the MRGPRD and the effect of sterol derivatives, i.e., cholesterol and bile acids, on the activation of MRGPRD were established. Furthermore, it was discovered that the MRGPRD was constitutive (ligand-independent) active. In addition, it was discovered that methyl-β-cyclodextrin, which is known to remove sterols from the plasma membrane, triggered the MRGPRD-mediated IL-6 release. Secondly, in an effort to deorphanize MRGPRs, it was established that cysteine protease cathepsin S activates MRGPRD and MRGPRF. Lastly, using biophysical and biochemical techniques such as luciferase complementation, bioluminescence resonance energy transfer, and co-immunoprecipitation assays, the heteromeric interactions between MRGPRE and MRGPRF were unambiguously detected. Overall, in this doctoral thesis, the primary objective was to improve understanding of the involvement of MRGPRs in inflammatory biology, the activation mechanisms of MRGPRs, and the oligomeric interaction of MRGPRs. |
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Language
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English
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Publication
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Antwerp
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University of Antwerp, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, Department of Veterinary Sciences
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2023
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ISBN
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978-90-5728-826-5
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Volume/pages
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xxxi, 187 p.
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Note
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Labro, Alain J. [Supervisor]
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van Ostade, Xaveer [Supervisor]
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Full text (open access)
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