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Interactions Fonctionnelles Entre Récepteurs À Peptide RF-Amide Et Caractérisation De Ligands Bifonctionnels Des Récepteurs Mu Opioïde Et NPFF

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Interactions Fonctionnelles Entre Récepteurs À Peptide RF-Amide Et Caractérisation De Ligands Bifonctionnels Des Récepteurs Mu Opioïde Et NPFF UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE des Sciences de la Vie et de la Santé UMR 7242 -Biotechnologie et signalisation cellulaire THÈSE En vue de l’obtention du DOCTORAT DE L’UNIVERSITE DE STRASBOURG Discipline : Pharmacologie Etude des interactions fonctionnelles entre les récepteurs à peptide RF-amide et caractérisation de ligands bifonctionnels des récepteurs mu opioïde et NPFF Présentée et soutenue par Armand DRIEU LA ROCHELLE Le 12 avril 2018 JURY Dr. SIMONIN Frédéric, Directeur de recherche, université de Strasbourg Directeur de Thèse Dr MORISSET-LOPEZ Séverine, Chargé de recherche, CBM, Orléans Rapporteur externe Dr. BELTRAMO Massimiliano, Directeur de recherche, Centre INRA Val de Loire Rapporteur externe Pr. GAVERIAUX-RUFF Claire, Professeur de l’université de Strasbourg Examinateur interne Remerciements Je souhaite tout d’abord adresser mes remerciements aux membres du jury pour avoir accepté d’évaluer mon travail, Dr. Séverine Morisser-Lopez, Pr. Claire Gavériaux-Ruff, Dr. Massimiliano Beltramo et Dr. Didier Rognan. Je voudrais également remercier Frédéric Simonin pour m’avoir accueilli dans son équipe, et pour son soutien dans la préparation du concours de l’école doctorale en Master 2. Merci pour le partage de tes connaissances, tant sur les mécanismes de l’hyperalgésie induite par les opiacés que sur les orchidées sauvages d’Alsace, merci pour ta disponibilité et pour l’autonomie que tu m’as accordée dans ces divers projets. Ma gratitude et ma reconnaissance vont à Brigitte Ilien, ton exigence et ta rigueur accompagnées de ta bonne humeur resteront un exemple pour moi. Merci à toi pour ces longues conversations de pharmacologie moléculaire, en particulier sur le FRET, qui m’ont tant appris et m’auront permis de construire un regard critique sur ce travail de thèse. Merci de m’avoir fait découvrir les grands de ce monde : Kenakin, Christopoulos, Vilardaga et Lohse (pour ne citer qu’eux). Mes remerciements vont également à tous les membres de l’équipe, Valérie Utard pour ton soutien technique et moral à toute épreuve, Sandra Lecat pour avoir pris le temps de corriger certains passages de ce manuscrit, et pour toutes ces critiques constructives en labmeeting qui ont contribué à faire avancer mes travaux. Je voudrais spécialement remercier Renaud Wagner et l’équipe d’IMPreSS (Valérie Kugler, Gabrielle Zeder-Lutz, Lucie Hartmann, Sarah Bouteben et ses prédécesseurs), pour la joie, la bonne humeur et l’expertise que vous m’avez partagé quand j’étais au plus mal dans mes clonages. Un hommage au « bureau des rousses » (Glenn, Raph et Lydia), lieu stratégique de remotivation et de débriefing en tout genre. Merci à Dayana, Laurent, Thibaud, Eleonora qui m’ont tenu compagnie dans ce bureau D319. Merci au Pr Vincent Phalip et Pr Claire Gavériaux-Ruff pour ces deux années d’assistant aux travaux pratiques d’enzymologie, vous accompagner dans cette mission d’enseignement fut pour moi une très belle expérience. Et plus largement au sein de l’ESBS et sur le campus d’Illkirch, je remercie le comité des fêtes et les jeunes doc’ post-doc’ pour tous ces bons moments, raclettes, BBQ et fêtes de Noël. Je remercie également la plateforme PCBIS, Pascal Villa, Sophie Gioria, Christel Valencia, ainsi que Patrick Gizzi et François Daubeuf pour m’avoir patiemment aidé, cette thèse n’aurait pas eu d’aussi beaux résultats sans vos conseils. Je voudrais également remercier Dr. Frédéric Bihel et Séverine Schneider pour ces collaborations fructueuses et ces échanges scientifiques. J’aurai aimé porter encore plus loin ces ligands fluorescents ! Je remercie Dr. Steven Ballet pour avoir su comprendre le potentiel du mystérieux KGFF09 et permis à cette histoire de voir le jour, et à Charlotte Martin pour sa réactivité à me ré-approvisionner en KGFF09. Enfin, je voudrais remercier tous ceux qui ont rendu ces années de doctorat strasbourgeois aussi magique : Alex évidemment, soutien infaillible moral et logistique, ces virées en ski de fond sur les crêtes et ces footing autour du lac pour oublier le RF9 ! Tes petits tup’ excellents et ta voiture m’ont fait gagner de précieuses heures et m’ont évité plusieurs pneumonies. Chaque page de ce manuscrit te revient de droit. Glenn et Raph pour tous ces petits moments magiques du quotidien qui ont égaillé ces trop longues heures passées au labo, ces trajets à vélo, et toutes ces soirées, ces journées à découvrir l’Alsace, ces week-ends passés avec la dream team strasbourgeoise (Hélène, Oriane, GG, Juju, Mélissa, Thibaut, Geek, Etza, Angie, Pierre). Tant de joies ! Vous mériteriez chacun une page de remerciements, mais il se fait tard… Pour finir, je voudrais remercier ma famille, mes parents et la fratrie pour leur soutien constant, et leurs encouragements. Cette thèse n’aurait pas été si bien écrite sans vos corrections, ni sans cette semaine de vacances à Gérardmer 1 semaine avant de rendre le manuscrit ! Je tiens à remercier également la mCherry pour m’avoir à ce point pourri ces années, et au NPFF2R pour m’avoir systématiquement tenu tête dans mes clonages. Mes nuits auraient définitivement été plus tranquilles sans vous, mes cernes moins grands et mes cheveux moins blancs. Même quand j’aurais Alzheimer je me souviendrai de vous et je continuerai à vous maudire. Comparé à vous, une manip au Brandel était presque agréable. Ma petite mémoire ne saurait redonner la liste exhaustive des personnes qui ont pu me prêter main forte, mais dans mon oubli je les remercie du fond du cœur. Table des matières Liste des tableaux Liste des figures Liste des abréviations INTRODUCTION I. Les récepteurs couplés aux protéines G ............................................................................ 1 1. Historique .............................................................................................................................................. 1 2. Généralités ............................................................................................................................................ 2 3. Activation et signalisation d’un récepteur couplé aux protéines G .................................. 3 3.1. La protéine G hétérotrimérique .................................................................................................................... 4 3.2. Les kinases associées au RCPG ...................................................................................................................... 5 3.3. La -arrestine ............................................................................................................................................... 7 4. Notion de ligand biaisé ..................................................................................................................... 8 4.1. Le récepteur à l’hormone parathyroïdienne, et régénération osseuse ...................................... 10 4.2. Les récepteurs -adrénergiques, et -bloquants ................................................................................. 10 4.3. Le récepteur à la dopamine D2, et antipsychotiques .......................................................................... 11 4.4. Le récepteur 1 à l’angiotensine II ............................................................................................................... 11 5. Interactions fonctionnelles et hétérodimérisation ............................................................. 12 5.1. Interactions non-spécifiques ........................................................................................................................ 13 5.2. Interactions spécifiques .................................................................................................................................. 14 5.3. Interactions complexes ................................................................................................................................... 17 II. Douleur et modulation du l’influx nociceptif ................................................................ 18 1. Physiologie de la douleur .............................................................................................................. 18 1.1. Stimulus nociceptif et intégration .............................................................................................................. 18 1.2. Modulation de la douleur, hypersensibilité à la douleur .................................................................. 20 2. Le système opioïdergique ............................................................................................................. 22 2.1. Les opiacés............................................................................................................................................................ 23 2.2. Les opioides endogènes .................................................................................................................................. 24 2.3. Les fonctions biologiques des récepteurs aux opioïdes .................................................................... 25 3. Prise en charge thérapeutique de la douleur ........................................................................ 31 3.1. Traitements actuels .......................................................................................................................................... 31 3.2. Limites des traitements actuels ................................................................................................................... 33 III. Le système RF-amide ............................................................................................................
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