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See detailTargeted mutagenesis of orphan GPCRs of the SREB family
Laschet, Céline ULiege; Dupuis, Nadine ULiege; Geubelle, Pierre ULiege et al

Poster (2017, September)

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See detailGPR101 orphan GPCR: a novel cause of growth hormone deregulation
Abboud, Dayana ULiege; Daly, Adrian ULiege; Dupuis, Nadine ULiege et al

Poster (2017, May)

GPR101 is an orphan G-protein coupled receptor with unknown ligand. In 2014, an international study clearly pointed to a strong association between this receptor and the X-linked acrogigantism (X-LAG ... [more ▼]

GPR101 is an orphan G-protein coupled receptor with unknown ligand. In 2014, an international study clearly pointed to a strong association between this receptor and the X-linked acrogigantism (X-LAG) syndrome, which begins in childhood and causes the “tallest giants”. The children (carriers of the GPR101 duplication on the X chromosome) grow abnormally even before they are one year old, secrete phenomenal quantities of growth hormone, and develop pituitary adenomas that do not respond to current therapies. The mechanism by which GPR101 contributes to increased growth hormone secretion is currently not known. Nevertheless, the lack of mechanistic insight into the function of GPR101 precludes its validation as a drug target. This lack of knowledge on GPR101 is the consequence of the paucity of specific pharmacological/research tools currently available. Therefore, we propose to study GPR101 functions and its role in growth hormone regulation. First, we determined the receptor cellular localization. We also deciphered its constitutive signalling pathways by detecting high cAMP levels. We completed our study with an examination of receptor coupling to other pathways and G proteins. Furthermore, we applied targeted mutagenesis to modulate the receptor constitutive activity in order to understand the receptor function at a molecular level. These GPR101 mutants will help us to understand the role of this receptor in GH regulation and/or to treat people suffering from pituitary dysfunction. This information is an absolute prerequisite to link molecular pharmacology of GPR101 with physiological functions. [less ▲]

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See detailDiscovery and pharmacological characterization of succinate receptor (SUCNR1/GPR91) agonists
Geubelle, Pierre ULiege; Gilissen, Julie; Dilly, Sebastien et al

in British Journal of Pharmacology (2017), 174(9), 796-808

Background and Purpose The succinate receptor (SUCNR1 or GPR91) has been described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho ... [more ▼]

Background and Purpose The succinate receptor (SUCNR1 or GPR91) has been described as a metabolic sensor that may be involved in homeostasis. Notwithstanding its implication in important (patho)physiological processes, the function of SUCNR1 has remained elusive because no pharmacological tools were available. We report on the discovery of the first family of synthetic potent agonists. Experimental Approach We screened a library of succinate analogues and analysed their activity on SUCNR1. In addition, we modelled a pharmacophore and a binding site for the receptor. New agonists were identified based on the information provided by these two approaches. Their activity was studied in various bioassays, including measurement of cAMP levels, [Ca2+]i mobilisation, TGF-α shedding and recruitment of arrestin 3. The in vivo impact of SUCNR1 activation by these new agonists was evaluated on rat blood pressure. Key Results We identified cis-epoxysuccinic acid and cis-1,2-cyclopropanedicarboxylic acid as agonists with an efficacy similar to the one of succinic acid. Interestingly, cis-epoxysuccinic acid was characterized by a 10 to 20 fold higher potency than succinate on the receptor. For example, cis-epoxysuccinic acid reduced cAMP levels with a pEC50 = 5.57 ± 0.02 (EC50 = 2.7 μM) as compared to succinate pEC50 = 4.54 ± 0.08 (EC50 = 29 μM). The rank order of potency of the three agonists was the same in all bioassays tested. In vivo, cis-epoxysuccinic and cis-1,2-cyclopropanedicarboxylic acid increased rat blood pressure to the same extent as succinate did. Conclusions and Implications We provide new agonist tools for SUCNR1 that should facilitate further research on this understudied receptor. [less ▲]

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See detailChemokine neutralization as an innovative therapeutic strategy for atopic dermatitis
Abboud, Dayana ULiege; Hanson, Julien ULiege

in Drug Discovery Today (2017), 22(4), 702-7011

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See detailSmall molecule ligands for the orphan GPR27
Dupuis, Nadine ULiege; Franssen, Delphine ULiege; Laschet, Céline ULiege et al

Poster (2016, September 26)

Background G protein-coupled receptors (GPCRs) are involved in many physiological processes and constitute the target of around 30% of marketed therapies. Nonetheless, ~100 human GPCRs have no known ... [more ▼]

Background G protein-coupled receptors (GPCRs) are involved in many physiological processes and constitute the target of around 30% of marketed therapies. Nonetheless, ~100 human GPCRs have no known ligand and are designated as "orphan". This project focuses on GPR27, a rhodopsin-like alpha orphan of the SREB family (Super conserved Receptors Expressed in the Brain), presumably involved in the regulation of insulin secretion [1]. Methods In order to identify small molecules activating GPR27, we developed a firefly luciferase complementation assay (based on [2]) to assess the binding of ß-arrestin2 to the activated GPCR. To increase the affinity for and strengthen the interaction with ß-arrestin2, a GPR27-V2R chimera has been used for library screening. Results Small molecules activating GPR27-V2 have been identified in the DiverSetTM library (ChemBridge). After exclusion of non-specific activities using another unrelated GPCR, two compounds sharing a common scaffold with activity in the low micromolar range were selected for further investigations. We confirmed their agonist profile by performing complete concentration-response curves on our arrestin complementation assay as well as orthogonal assays. These compounds show good specificity being inactive on GPR85-V2 and GPR173-V2 (the two other SREB members). With these original tools, we characterized the recruitment of ß-arrestin2 to activated GPR27 WT. Conclusion We identified small molecule ligands for GPR27 that will serve as valuable tools for studying the pharmacology of GPR27 as well as its physiological roles, for example in insulin secretion. 1 Ku G.M., Pappalardo Z., Luo C.C., German M.S., McManus M.T. An siRNA Screen in Pancreatic Beta Cells Reveals a Role for Gpr27 in Insulin Production. PLoS genetics. 2012, 8, e1002449. 2 Takakura H., Hattori M., Takeuchi M., Ozawa T. Visualization and Quantitative Analysis of G Protein-Coupled Receptor−β-Arrestin Interaction in Single Cells and Specific Organs of Living Mice Using Split Luciferase Complementation. ACS Chem. Biol. 2012, 7, 901−910. [less ▲]

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See detailTargeted mutagenesis of orphan GPCRs of the SREB family
Laschet, Céline ULiege; Dupuis, Nadine ULiege; Soni, Arvind ULiege et al

Poster (2016, September)

Detailed reference viewed: 18 (12 ULiège)