6 results on '"Justine S. Paradis"'
Search Results
2. Effect of the Metabotropic Glutamate Receptor Type 5 Negative Allosteric Modulator Dipraglurant on Motor and Non-Motor Symptoms of Parkinson’s Disease
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Mark P. Epping-Jordan, Françoise Girard, Anne-Sophie Bessis, Vincent Mutel, Christelle Boléa, Francis Derouet, Abdelhak Bessif, Brice Mingard, Stéphanie Barbier, Justine S. Paradis, Jean-Philippe Rocher, Robert Lütjens, Mikhail Kalinichev, and Sonia Poli
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dipraglurant ,mGlu5 ,depression ,anxiety ,obsessive-compulsive disorder ,Parkinson’s disease ,Cytology ,QH573-671 - Abstract
Parkinson’s disease (PD) patients suffer not only from the primary motor symptoms of the disease but also from a range of non-motor symptoms (NMS) that cause disability and low quality of life. Excessive glutamate activity in the basal ganglia resulting from degeneration of the nigrostriatal dopamine pathway has been implicated in the motor symptoms, NMS and dyskinesias in PD patients. In this study, we investigated the effects of a selective mGlu5 negative allosteric modulator (NAM), dipraglurant, in a rodent motor symptoms model of PD, but also in models of anxiety, depression and obsessive-compulsive disorder, all of which are among the most prevalent NMS symptoms. Dipraglurant is rapidly absorbed after oral administration, readily crosses the blood-brain barrier, and exhibits a high correlation between plasma concentration and efficacy in behavioral models. In vivo, dipraglurant dose-dependently reduced haloperidol-induced catalepsy, increased punished licks in the Vogel conflict-drinking model, decreased immobility time in the forced swim test, decreased the number of buried marbles in the marble-burying test, but had no effect on rotarod performance or locomotor activity. These findings suggest that dipraglurant may have benefits to address some of the highly problematic comorbid non-motor symptoms of PD, in addition to its antidyskinetic effect demonstrated in PD-LID patients.
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- 2023
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3. A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling
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Alexandre Beautrait, Justine S. Paradis, Brandon Zimmerman, Jenna Giubilaro, Ljiljana Nikolajev, Sylvain Armando, Hiroyuki Kobayashi, Lama Yamani, Yoon Namkung, Franziska M. Heydenreich, Etienne Khoury, Martin Audet, Philippe P. Roux, Dmitry B. Veprintsev, Stéphane A. Laporte, and Michel Bouvier
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Science - Abstract
Beta-arrestins play central roles in the mechanisms regulating GPCR signalling and trafficking. Here the authors identify a selective inhibitor of the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP-2, which they use to dissect the role of the β-arrestin/β2-adaptin interaction in GPCR signalling.
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- 2017
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4. Establishment of a novel cancer cell line derived from vulvar carcinoma associated with lichen sclerosus exhibiting a fibroblast-dependent tumorigenic potential
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Justine S. Paradis, Neha Rana, Harsh Dongre, Anne Christine Johannessen, Saroj Rajthala, J. Silvio Gutkind, Ingeborg B. Engelsen, Line Bjørge, Daniela Elena Costea, Siren Fromreide, and Olav Karsten Vintermyr
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0301 basic medicine ,endocrine system ,Vulvar Squamous Cell Carcinoma ,Carcinogenesis ,Cell Culture Techniques ,Mice, SCID ,Lichen sclerosus ,Biology ,medicine.disease_cause ,Vulvar Lichen Sclerosus ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,Mice, Inbred NOD ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Clonogenic assay ,Cells, Cultured ,Vulvar Neoplasms ,Cell Biology ,Fibroblasts ,medicine.disease ,Xenograft Model Antitumor Assays ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,Carcinoma, Squamous Cell ,Female ,Vulvar Carcinoma ,Immortalised cell line - Abstract
Vulvar squamous cell carcinoma associated with lichen sclerosus (VLS-VSCC) are rare tumors but with higher recurrence and worse prognosis than other types of VSCC. Lack of experimental models has limited the search for better understanding of the biology and development of treatment modalities. In this study, we isolated and characterized primary cells from VSCC (n = 7) and normal vulvar tissue adjacent to tumor (n = 7). Detailed characterization of the novel spontaneously immortalized cell line, VCC1 revealed a characteristic epithelial morphology in vitro and a well-differentiated keratinizing SCC histology in vivo, closely resembling the tumor of origin. VCC1 expressed higher levels of epithelial-mesenchymal transition markers and higher clonogenic properties as compared to other established non VLS-VSCC cell lines. In vitro 3D organotypic assays and in vivo xenografts revealed a prominent role of cancer-associated fibroblasts in VCC1 invasion and tumor formation. In conclusion, VCC1 mirrored several major VLS-VSCC features and provided a robust experimental tool for further elucidation of VLS-related oncogenesis and drug testing. publishedVersion
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- 2020
5. A new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling
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Philippe P. Roux, Sylvain Armando, Etienne Khoury, Alexandre Beautrait, Hiroyuki Kobayashi, Michel Bouvier, Justine S. Paradis, Brandon Zimmerman, Franziska M. Heydenreich, Yoon Namkung, Dmitry B. Veprintsev, Stéphane A. Laporte, Martin Audet, Lama Yamani, Jenna Giubilaro, and Ljiljana Nikolajev
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0301 basic medicine ,genetic structures ,Science ,media_common.quotation_subject ,Endocytic cycle ,General Physics and Astronomy ,Endocytosis ,Clathrin ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Article ,Receptors, G-Protein-Coupled ,Small Molecule Libraries ,03 medical and health sciences ,0302 clinical medicine ,Arrestin ,Cyclic AMP ,Animals ,Humans ,Adaptor Protein Complex beta Subunits ,Internalization ,Extracellular Signal-Regulated MAP Kinases ,beta-Arrestins ,media_common ,G protein-coupled receptor ,Multidisciplinary ,biology ,Chemistry ,Beta-Arrestins ,Cell Membrane ,Clathrin-Coated Vesicles ,General Chemistry ,eye diseases ,3. Good health ,Cell biology ,Rats ,Enzyme Activation ,030104 developmental biology ,HEK293 Cells ,biology.protein ,sense organs ,Signal transduction ,030217 neurology & neurosurgery ,Protein Binding ,Signal Transduction - Abstract
In addition to G protein-coupled receptor (GPCR) desensitization and endocytosis, β-arrestin recruitment to ligand-stimulated GPCRs promotes non-canonical signalling cascades. Distinguishing the respective contributions of β-arrestin recruitment to the receptor and β-arrestin-promoted endocytosis in propagating receptor signalling has been limited by the lack of selective analytical tools. Here, using a combination of virtual screening and cell-based assays, we have identified a small molecule that selectively inhibits the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP2 without interfering with the formation of receptor/β-arrestin complexes. This selective β-arrestin/β2-adaptin inhibitor (Barbadin) blocks agonist-promoted endocytosis of the prototypical β2-adrenergic (β2AR), V2-vasopressin (V2R) and angiotensin-II type-1 (AT1R) receptors, but does not affect β-arrestin-independent (transferrin) or AP2-independent (endothelin-A) receptor internalization. Interestingly, Barbadin fully blocks V2R-stimulated ERK1/2 activation and blunts cAMP accumulation promoted by both V2R and β2AR, supporting the concept of β-arrestin/AP2-dependent signalling for both G protein-dependent and -independent pathways., Beta-arrestins play central roles in the mechanisms regulating GPCR signalling and trafficking. Here the authors identify a selective inhibitor of the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP-2, which they use to dissect the role of the β-arrestin/β2-adaptin interaction in GPCR signalling.
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- 2017
6. Receptor sequestration in response to β-arrestin-2 phosphorylation by ERK1/2 governs steady-state levels of GPCR cell-surface expression
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Hervé Enslen, Justine S. Paradis, Mark G. H. Scott, Stevenson Ly, Alexandre Beautrait, Elodie Blondel-Tepaz, Philippe P. Roux, Michel Bouvier, Stefano Marullo, Jacob A. Galan, Enslen, Hervé, Université de Montréal (UdeM), Institut Cochin (IC UM3 (UMR 8104 / U1016)), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité)
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MAPK/ERK pathway ,Cell signaling ,Cytoplasm ,Arrestins ,MAP Kinase Signaling System ,[SDV]Life Sciences [q-bio] ,Molecular Sequence Data ,Receptors, Prostaglandin ,Ligands ,Receptor tyrosine kinase ,Receptors, G-Protein-Coupled ,Chemokine receptor ,Mice ,cell signaling ,Animals ,Humans ,G protein-coupled receptor ,Amino Acid Sequence ,Phosphorylation ,Receptor ,beta-Arrestins ,Mitogen-Activated Protein Kinase 1 ,Multidisciplinary ,Mitogen-Activated Protein Kinase 3 ,β-arrestin ,biology ,Sequence Homology, Amino Acid ,Beta-Arrestins ,Cell Membrane ,Fibroblasts ,MAPK ,beta-Arrestin 2 ,Cell biology ,internalization ,[SDV] Life Sciences [q-bio] ,Enzyme Activation ,HEK293 Cells ,PNAS Plus ,biology.protein ,Cattle ,Signal transduction ,Peptides ,hormones, hormone substitutes, and hormone antagonists ,HeLa Cells ,Protein Binding ,Signal Transduction - Abstract
International audience; MAPKs are activated in response to G protein-coupled receptor (GPCR) stimulation and play essential roles in regulating cellular processes downstream of these receptors. However, very little is known about the reciprocal effect of MAPK activation on GPCRs. To investigate possible crosstalk between the MAPK and GPCRs, we assessed the effect of ERK1/2 on the activity of several GPCR family members. We found that ERK1/2 activation leads to a reduction in the steady-state cell-surface expression of many GPCRs because of their intracellular sequestration. This subcellular redistribution resulted in a global dampening of cell responsiveness, as illustrated by reduced ligand-mediated G-protein activation and second-messenger generation as well as blunted GPCR kinases and β-arrestin recruitment. This ERK1/2-mediated regulatory process was observed for GPCRs that can interact with β-arrestins, such as type-2 vasopressin, type-1 angiotensin, and CXC type-4 chemokine receptors, but not for the prostaglandin F receptor that cannot interact with β-arrestin, implicating this scaffolding protein in the receptor's subcellular redistribution. Complementation experiments in mouse embryonic fibroblasts lacking β-arrestins combined with in vitro kinase assays revealed that β-arrestin-2 phosphorylation on Ser14 and Thr276 is essential for the ERK1/2-promoted GPCR sequestration. This previously unidentified regulatory mechanism was observed after constitutive activation as well as after receptor tyrosine kinase- or GPCR-mediated activation of ERK1/2, suggesting that it is a central node in the tonic regulation of cell responsiveness to GPCR stimulation, acting both as an effector and a negative regulator.
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- 2015
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