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Contribution Du Récepteur 5-HT2B Dans La Transmission Sérotoninergique

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Contribution Du Récepteur 5-HT2B Dans La Transmission Sérotoninergique Université Pierre et Marie Curie Ecole doctorale Physiologie, physiopathologie et thérapeutique (P2T) Laboratoire INSERM U839 / Equipe de recherche Luc Maroteaux : Signalisation de la sérotonine dans la plasticité et la pathologie Contribution du récepteur 5-HT2B dans la transmission sérotoninergique Par Emily QUENTIN Thèse de doctorat de Neurosciences Dirigée par Luc Maroteaux Présentée et soutenue publiquement le 12 Juillet 2017 Devant un jury composé de : M. Salah El Mestikawy, Directeur de recherche Président du Jury Mme. Françoise Coussen, Directeur de recherche Rapporteur Mme. Michèle Darmon, Directeur de recherche Rapporteur Mme. Sabine Lévi, Directeur de recherche Examinateur M. Philippe Marin, Directeur de recherche Examinateur -2- TABLE DES MATIERES TABLE DES MATIERES .............................................................................................................................. 3 TABLE DES ABREVIATIONS ....................................................................................................................... 7 INDEX DES FIGURES ................................................................................................................................. 9 RESUME ................................................................................................................................................. 13 ABSTRACT .............................................................................................................................................. 13 AVANT PROPOS ..................................................................................................................................... 14 INTRODUCTION ..................................................................................................................................... 17 I. Le système sérotoninergique ........................................................................................................ 18 A. Généralités ............................................................................................................................ 18 1. Découverte de la sérotonine ............................................................................................. 18 2. Métabolisme de la sérotonine .......................................................................................... 19 3. Organisation des neurones sérotoninergiques ................................................................. 20 B. Acteurs de la transmission sérotoninergique........................................................................ 22 1. Le transporteur de la sérotonine SERT .............................................................................. 22 i. Distribution .................................................................................................................. 23 ii. Régulations .................................................................................................................. 23 2. Les récepteurs sérotoninergiques ..................................................................................... 25 i. Les R-5-HT1A et 5-HT1B ................................................................................................. 27 ii. Les R-5-HT2A/2C ............................................................................................................. 28 iii. Les autres R-5-HT ........................................................................................................ 30 iv. Oligomérisation ........................................................................................................... 32 Homodimères .................................................................................................................... 32 Hétérodimères ................................................................................................................... 32 C. Protéines associées aux récepteurs sérotoninergiques ........................................................ 35 1. Protéines PDZ .................................................................................................................... 35 2. Protéines PDZ associées aux R-5-HT.................................................................................. 37 3. Autres protéines (GRK-b-arrestine, canaux ioniques, Yif, CAM) ....................................... 38 4. CIPP .................................................................................................................................... 39 II. Le récepteur 5-HT2B ....................................................................................................................... 43 A. Généralités ............................................................................................................................ 43 B. Caractérisation fonctionnelle des mutants du récepteur 5-HT2B .......................................... 47 1. Contribution de l’extrémité C-terminale ........................................................................... 47 i. Gain de fonction du mutant R393X ............................................................................. 47 -3- ii. Perte de fonction du mutant R388W .......................................................................... 47 2. Contribution de l’extrémité N-terminale .......................................................................... 48 i. Phénotype du polymorphisme R6G ; E42G ................................................................. 48 C. Interactions du récepteur 5-HT2B .......................................................................................... 48 1. Les récepteurs 5-HT1B et 5-HT2B ......................................................................................... 48 2. Modulation de SERT par le couplage 5-HT2B / NOS ........................................................... 49 D. Fonctions physiologiques et pathologiques du R-5-HT2B ...................................................... 49 1. Au niveau périphérique ..................................................................................................... 49 2. Au niveau central ............................................................................................................... 51 3. Contribution du récepteur 5-HT2B dans les pathologies psychiatriques ........................... 51 i. Prise alimentaire ......................................................................................................... 51 ii. Impulsivité ................................................................................................................... 52 iii. Schizophrénie .............................................................................................................. 53 iv. Vulnérabilité aux drogues d’abus ................................................................................ 54 - Cocaïne ........................................................................................................................ 54 - Ecstasy ou MDMA (3,4-methylenedioxymethamphetamine) ..................................... 55 v. Dépression- Inhibiteurs sélectifs de la recapture de la sérotonine (ISRSs) ................. 56 III. Transmission sérotoninergique ................................................................................................. 59 A. Mode de neurotransmission ................................................................................................. 59 B. Libération de la sérotonine ................................................................................................... 61 1. Libération synaptique de sérotonine ................................................................................ 62 2. Libération extrasynaptique de sérotonine ........................................................................ 62 i. Somatodendritique ..................................................................................................... 63 ii. Dendritique ................................................................................................................. 64 C. Modulation de la transmission sérotoninergique ................................................................. 67 1. Hétéro-régulation .............................................................................................................. 67 i. Par les neurones glutamatergiques et GABAergiques ................................................ 67 ii. Co-libération de glutamate ......................................................................................... 69 iii. Régulation par les R-5-HT1A et 5-HT2 ........................................................................... 71 2. Autorégulation par les R-5-HT1 et les R-5-HT2 ................................................................... 72 OBJECTIFS DE L’ETUDE .......................................................................................................................... 77 RESULTATS ............................................................................................................................................. 81 1. LE RECEPTEUR 5-HT2B : UN MODULATEUR POSITIF DE L’ACTIVITE DES NEURONES SEROTONINERGIQUES ......................... 85 5-HTKO A. Caractérisation des animaux 5-HT2B .............................................................................. 85 B. Le R-5-HT2B participe à l’activité des neurones sérotoninergiques ....................................... 87 C. Dualité fonctionnelle des R-5-HT1A et des R-5-HT2B .............................................................
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