References of "Dupuis, Nadine"
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See detailGPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11
Abboud, Dayana ULiege; Daly, Adrian ULiege; Dupuis, Nadine ULiege et al

in Nature Communications (2020), 11(1), 4752

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over ... [more ▼]

Growth hormone (GH) is a key modulator of growth and GH over-secretion can lead to gigantism. One form is X-linked acrogigantism (X-LAG), in which infants develop GH-secreting pituitary tumors over-expressing the orphan G-protein coupled receptor, GPR101. The role of GPR101 in GH secretion remains obscure. We studied GPR101 signaling pathways and their effects in HEK293 and rat pituitary GH3 cell lines, human tumors and in transgenic mice with elevated somatotrope Gpr101 expression driven by the rat Ghrhr promoter (GhrhrGpr101). Here, we report that Gpr101 causes elevated GH/prolactin secretion in transgenic GhrhrGpr101 mice but without hyperplasia/tumorigenesis. We show that GPR101 constitutively activates not only Gs, but also Gq/11 and G12/13, which leads to GH secretion but not proliferation. These signatures of GPR101 signaling, notably PKC activation, are also present in human pituitary tumors with high GPR101 expression. These results underline a role for GPR101 in the regulation of somatotrope axis function. [less ▲]

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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 detailActivation of the orphan G protein-coupled receptor GPR27 by surrogate ligands promotes β-arrestin 2 recruitment
Dupuis, Nadine ULiege; Laschet, Céline ULiege; Franssen, Delphine ULiege et al

in Molecular Pharmacology (2017), 91(6), 595-608

G protein-coupled receptors are the most important drug targets for human diseases. An important number of them remain devoid of confirmed ligands. GPR27 is one of these orphan receptors, characterized by ... [more ▼]

G protein-coupled receptors are the most important drug targets for human diseases. An important number of them remain devoid of confirmed ligands. GPR27 is one of these orphan receptors, characterized by a high level of conservation among vertebrates and a predominant expression in the central nervous system. In addition, it has recently been linked to insulin secretion. However, the absence of endogenous or surrogate ligands for GPR27 complicates the examination of its biological function. Our aim was to validate GPR27 signaling pathways and therefore we sought to screen a diversity oriented synthesis library to identify GPR27-specific surrogate agonists. In order to select an optimal screening assay, we investigated GPR27 ligand-independent activity. Both in G protein-mediated pathways and in β-arrestin 2 recruitment, no ligand-independent activity could be measured. However, we observed a recruitment of β-arrestin 2 to a GPR27V2 chimera in the presence of membrane-anchored β-adrenergic receptor kinase 1 (GRK2). Therefore, we optimized a firefly luciferase complementation assay to screen against this chimeric receptor. We identified two compounds (N-[4-(anilinocarbonyl)phenyl]-2,4-dichlorobenzamide (ChemBridge ID5128535) and 2,4-dichloro-N-{4-[(1,3-thiazol-2-ylamino)sulfonyl]phenyl}benzamide (ChemBridge ID5217941)) sharing a N-phenyl-2,4-dichlorobenzamide scaffold, which were selective for GPR27 over its closely related family members GPR85 and GPR173. The specificity of the activity was confirmed with a NanoBiT® β-arrestin 2 assay, imaging of GFP-tagged β-arrestin 2 and PathHunter® β-arrestin 2 Assay. Interestingly, no G protein activation was detected upon activation of GPR27 by these compounds. Our study provides the first selective surrogate agonists for the orphan GPR27. [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 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 detailGPR101 orphan GPCR: a novel cause of growth hormone deregulation
Abboud, Dayana ULiege; Daly, Adrian ULiege; Dupuis, Nadine ULiege et al

Poster (2017, April)

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

Poster (2016, November)

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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)

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See detailHuman herpesvirus 8-encoded chemokine vCCL2/vMIP-II is an agonist of the atypical chemokine receptor ACKR3/CXCR7
Szpakowska, Martyna; Dupuis, Nadine ULiege; Baragli, Alessandra et al

in Biochemical Pharmacology (2016), 114

Detailed reference viewed: 44 (9 ULiège)
See detailIdentification of small molecule ligands for the orphan GPCR GPR27
Dupuis, Nadine ULiege; Gilissen, Julie; Derj, Anouar ULiege et al

Poster (2016, January 25)

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See detailTargeted and random mutagenesis of orphan GPCRs of the SREB family
Laschet, Céline ULiege; Dupuis, Nadine ULiege; Derj, Anouar ULiege et al

Poster (2016, January 25)

Detailed reference viewed: 38 (3 ULiège)
See detailßarrestin coupling of the orphan GPCR GPR27
Dupuis, Nadine ULiege; Gilissen, Julie ULiege; Derj, Anouar ULiege et al

Poster (2015, January 27)

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See detailIdentification, Design and Evaluation of Pharmacological tools for the orphan GPCR GPR22
Geubelle, Pierre ULiege; Gilissen, Julie ULiege; Dupuis, Nadine ULiege et al

Poster (2015, January 27)

GPCRs are the largest family of membrane receptors and are characterized by 7 transmembrane domains. GPR22 is a GPCR that has no known endogenous ligand and is thus considered "orphan". Its presence ... [more ▼]

GPCRs are the largest family of membrane receptors and are characterized by 7 transmembrane domains. GPR22 is a GPCR that has no known endogenous ligand and is thus considered "orphan". Its presence situated at the heart and brain levels makes it a potential target for new therapeutic pathways. This study consist in the identification of a synthetic ligand of GPR22 receptor to use it as a pharmacological tool in the study of the signaling channels of GPR22 in order to understand its role and to validate it as a new therapeutic target. The initial hypothesis was that GPR22 is coupled to the Gαi protein. [less ▲]

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See detailForskolin-free cAMP assay for Gi-coupled receptors
Gilissen, Julie ULiege; Geubelle, Pierre ULiege; Dupuis, Nadine ULiege et al

in Biochemical Pharmacology (2015)

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See detailIdentification, Design and Evaluation of Pharmacological tools for the orphan GPCR GPR22
Geubelle, Pierre ULiege; Gilissen, Julie ULiege; Dupuis, Nadine ULiege et al

Poster (2014, November 21)

GPCRs are the largest family of membrane receptors and are characterized by seven transmembrane domains. This family of receptors is currently the most successfully targeted protein for therapeutic ... [more ▼]

GPCRs are the largest family of membrane receptors and are characterized by seven transmembrane domains. This family of receptors is currently the most successfully targeted protein for therapeutic purposes. GPR22 is a GPCR that was discovered in 1997. It has no known endogenous ligand and is thus considered "orphan". Its presence situated at the heart and brain levels makes it a potential target for new therapeutic pathways. The only information about its signaling channel could be its coupling with G proteins. This study consist in the identification of a synthetic ligand of GPR22 receptor to use it as a pharmacological tool in the study of the signaling channels of GPR22 in order to understand its role and to validate it as a new therapeutic target. The initial hypothesis was that GPR22 is coupled to the Gαi protein. [less ▲]

Detailed reference viewed: 114 (7 ULiège)