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3 results on '"Chayma El Khamlichi"'

1. Bioluminescence Resonance Energy Transfer as a Method to Study Protein-Protein Interactions: Application to G Protein Coupled Receptor Biology

Author

Chayma El Khamlichi, Flora Reverchon-Assadi, Nadège Hervouet-Coste, Lauren Blot, Eric Reiter, and Séverine Morisset-Lopez

Subjects
BRET, receptor-protein interactions, G protein-coupled receptors, GPCR signaling, GPCR-interacting proteins, drug discovery, screening, Organic chemistry, QD241-441
Abstract

The bioluminescence resonance energy transfer (BRET) approach involves resonance energy transfer between a light-emitting enzyme and fluorescent acceptors. The major advantage of this technique over biochemical methods is that protein-protein interactions (PPI) can be monitored without disrupting the natural environment, frequently altered by detergents and membrane preparations. Thus, it is considered as one of the most versatile technique for studying molecular interactions in living cells at “physiological„ expression levels. BRET analysis has been applied to study many transmembrane receptor classes including G-protein coupled receptors (GPCR). It is well established that these receptors may function as dimeric/oligomeric forms and interact with multiple effectors to transduce the signal. Therefore, they are considered as attractive targets to identify PPI modulators. In this review, we present an overview of the different BRET systems developed up to now and their relevance to identify inhibitors/modulators of protein⁻protein interaction. Then, we introduce the different classes of agents that have been recently developed to target PPI, and provide some examples illustrating the use of BRET-based assays to identify and characterize innovative PPI modulators in the field of GPCRs biology. Finally, we discuss the main advantages and the limits of BRET approach to characterize PPI modulators.

Published
2019
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2. Serodolin, a β-arrestin–biased ligand of 5-HT 7 receptor, attenuates pain-related behaviors

Author

Chayma El Khamlichi, Flora Reverchon, Nadège Hervouet-Coste, Elodie Robin, Nicolas Chopin, Emmanuel Deau, Fahima Madouri, Cyril Guimpied, Cyril Colas, Arnaud Menuet, Asuka Inoue, Andrzej J. Bojarski, Gérald Guillaumet, Franck Suzenet, Eric Reiter, Séverine Morisset-Lopez, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie Organique et Analytique (ICOA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), Tohoku University [Sendai], Polish Academy of Sciences (PAN), Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Dynamiques de populations multi-échelles pour des systèmes physiologiques (MUSCA), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Physiologie de la reproduction et des comportements [Nouzilly] (PRC), Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut Français du Cheval et de l'Equitation [Saumur] (IFCE)-Université de Tours (UT)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), ANR-10-LABX-0053,MAbImprove,Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used(2010), ANR-11-LABX-0029,SYNORG,Synthèse Organique : des molécules au vivant(2011), ANR-11-LABX-0018,IRON,Radiopharmaceutiques Innovants en Oncologie et Neurologie(2011), Reiter, Eric, Laboratoires d'excellence - Optimization of therapeutic monoclonal antibodies development Better antibodies, better developed AND better used - - MAbImprove2010 - ANR-10-LABX-0053 - LABX - VALID, Synthèse Organique : des molécules au vivant - - SYNORG2011 - ANR-11-LABX-0029 - LABX - VALID, and Radiopharmaceutiques Innovants en Oncologie et Neurologie - - IRON2011 - ANR-11-LABX-0018 - LABX - VALID

Subjects
[SDV] Life Sciences [q-bio], Multidisciplinary, GPCR, biased ligands, [SDV]Life Sciences [q-bio], 5-HT7 receptor, analgesia, serotonin
Abstract

Significance Transmembrane signaling through G protein–coupled receptors (GPCRs), originally described as requiring coupling to intracellular G proteins, also uses G protein–independent pathways through β-arrestin recruitment. Biased ligands, by favoring one of the multiple bioactive conformations of GPCRs, allow selective signaling through either of these pathways. Here, we identified Serodolin as the first β-arrestin–biased agonist of the serotonin 5-HT 7 receptor. This new ligand, while acting as an inverse agonist on G s signaling, selectively induces ERK activation in a β-arrestin–dependent way. Importantly, we report that Serodolin decreases pain intensity caused by thermal, mechanical, or inflammatory stimuli. Our findings suggest that targeting the 5-HT 7 R with β-arrestin–biased ligand could be a valid alternative strategy to the use of opioids for the relief of pain.

Published
2022
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3. BRET Analysis of GPCR Dimers in Neurons and Non-Neuronal Cells: Evidence for Inactive, Agonist, and Constitutive Conformations

Author

Chayma El Khamlichi, Jean-Michel Arrang, L. Cobret, Séverine Morisset-Lopez, Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Unité de Neurobiologie et Pharmacologie Moléculaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Frapart, Isabelle, and Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Bioluminescence Resonance Energy Transfer Techniques, Male, Intrinsic activity, Protein Conformation, [SDV]Life Sciences [q-bio], Ligands, Receptors, G-Protein-Coupled, 0302 clinical medicine, GPCR, H3R, Biology (General), Receptor, Spectroscopy, Cerebral Cortex, Neurons, 0303 health sciences, dimerization, Chemistry, General Medicine, Transfection, Recombinant Proteins, Computer Science Applications, [SDV] Life Sciences [q-bio], Agonist, medicine.drug_class, QH301-705.5, brain, Allosteric regulation, Article, Catalysis, Inorganic Chemistry, 03 medical and health sciences, medicine, Animals, Humans, Receptors, Histamine H3, Inverse agonist, Rats, Wistar, Physical and Theoretical Chemistry, Molecular Biology, QD1-999, constitutive activity, 030304 developmental biology, G protein-coupled receptor, Cell Membrane, Organic Chemistry, HEK 293 cells, Rats, HEK293 Cells, Biophysics, BRET, 030217 neurology & neurosurgery
Abstract

G-protein-coupled receptors (GPCRs) are dimeric proteins, but the functional consequences of the process are still debated. Active GPCR conformations are promoted either by agonists or constitutive activity. Inverse agonists decrease constitutive activity by promoting inactive conformations. The histamine H3 receptor (H3R) is the target of choice for the study of GPCRs because it displays high constitutive activity. Here, we study the dimerization of recombinant and brain H3R and explore the effects of H3R ligands of different intrinsic efficacy on dimerization. Co-immunoprecipitations and Western blots showed that H3R dimers co-exist with monomers in transfected HEK 293 cells and in rodent brains. Bioluminescence energy transfer (BRET) analysis confirmed the existence of spontaneous H3R dimers, not only in living HEK 293 cells but also in transfected cortical neurons. In both cells, agonists and constitutive activity of the H3R decreased BRET signals, whereas inverse agonists and GTPγS, which promote inactive conformations, increased BRET signals. These findings show the existence of spontaneous H3R dimers not only in heterologous systems but also in native tissues, which are able to adopt a number of allosteric conformations, from more inactive to more active states.

Published
2021
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