In vivo delta opioid receptor internalization controls behavioral effects of agonists
| Autor: | Claire Gaveriaux-Ruff, Grégory Scherrer, Brigitte L. Kieffer, Jérôme A.J. Becker, Dominique Filliol, Audrey Matifas, Amynah A. Pradhan, Dominique Massotte, Petra Tryoen-Toth |
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| Přispěvatelé: | Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This research was supported by the CNRS, INSERM, the University Louis Pasteur, Strasbourg, the French ANR grant IMOP and US NIH NIDA grant #DA05010. AP was supported by INSERM-FRSQ, ANR: IMOP,IMOP, ANR-07-NEUR-0016,IMOP,Imagerie fonctionnelle in vivo des récepteurs aux opiacés mu et delta: dynamique des récepteurs et adaptations aux drogues d'abus(2007), Peney, Maité, Neurosciences, Neurologie et psychiatrie - Imagerie fonctionnelle in vivo des récepteurs aux opiacés mu et delta: dynamique des récepteurs et adaptations aux drogues d'abus - - IMOP2007 - ANR-07-NEUR-0016 - NEURO - VALID |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Protein Conformation
Recombinant Fusion Proteins Cell Biology/Neuronal Signaling Mechanisms Green Fluorescent Proteins Biological Transport Active Pain lcsh:Medicine Neuropeptide FF receptor Mice Transgenic In Vitro Techniques Pharmacology Biology Ligands Piperazines Cell Biology/Cell Signaling 5-HT7 receptor δ-opioid receptor Mice 03 medical and health sciences 0302 clinical medicine Piperidines Receptors Opioid delta Homologous desensitization Dopamine receptor D2 Neuroscience/Neuronal Signaling Mechanisms [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology Enzyme-linked receptor Animals [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Phosphorylation lcsh:Science Cells Cultured 030304 developmental biology Insulin-like growth factor 1 receptor Neurons 0303 health sciences Multidisciplinary Sigma-1 receptor Behavior Animal Neuroscience/Sensory Systems Cell Membrane lcsh:R Benzamides lcsh:Q 030217 neurology & neurosurgery Research Article Neuroscience |
| Zdroj: | PLoS ONE PLoS ONE, Public Library of Science, 2009, 4 (5), pp.e5425. ⟨10.1371/journal.pone.0005425⟩ PLoS ONE, 2009, 4 (5), pp.e5425. ⟨10.1371/journal.pone.0005425⟩ PLoS ONE, Vol 4, Iss 5, p e5425 (2009) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0005425⟩ |
| Popis: | Background: GPCRs regulate a remarkable diversity of biological functions, and are thus often targeted for drug therapies. Stimulation of a GPCR by an extracellular ligand triggers receptor signaling via G proteins, and this process is highly regulated. Receptor activation is typically accompanied by desensitization of receptor signaling, a complex feedback regulatory process of which receptor internalization is postulated as a key event. The in vivo significance of GPCR internalization is poorly understood. In fact, the majority of studies have been performed in transfected cell systems, which do not adequately model physiological environments and the complexity of integrated responses observed in the whole animal. Methods and Findings: In this study, we used knock-in mice expressing functional fluorescent delta opioid receptors (DOReGFP) in place of the native receptor to correlate receptor localization in neurons with behavioral responses. We analyzed the pain-relieving effects of two delta receptor agonists with similar signaling potencies and efficacies, but distinct internalizing properties. An initial treatment with the high (SNC80) or low (AR-M100390) internalizing agonist equally reduced CFA-induced inflammatory pain. However, subsequent drug treatment produced highly distinct responses. Animals initially treated with SNC80 showed no analgesic response to a second dose of either delta receptor agonist. Concomitant receptor internalization and G-protein uncoupling were observed throughout the nervous system. This loss of function was temporary, since full DOR-eGFP receptor responses were restored 24 hours after SNC80 administration. In contrast, treatment with AR-M100390 resulted in retained analgesic response to a subsequent agonist injection, and ex vivo analysis showed that DOR-eGFP receptor remained G protein-coupled on the cell surface. Finally SNC80 but not AR-M100390 produced DOR-eGFP phosphorylation, suggesting that the two agonists produce distinct active receptor conformations in vivo which likely lead to differential receptor trafficking. Conclusions: Together our data show that delta agonists retain full analgesic efficacy when receptors remain on the cell surface. In contrast, delta agonist-induced analgesia is abolished following receptor internalization, and complete behavioral desensitization is observed. Overall these results establish that, in the context of pain control, receptor localization fully controls receptor function in vivo. This finding has both fundamental and therapeutic implications for slow-recycling GPCRs. Citation: Pradhan AAA, Becker JAJ, Scherrer G, Tryoen-Toth P, Filliol D, et al. (2009) In Vivo Delta Opioid Receptor Internalization Controls Behavioral Effects of |
| Databáze: | OpenAIRE |
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