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V. I. Chapitre, Conclusion générale

, Le senseur calcique otoferline, ainsi que les canaux calciques Cav1.3 présents à la membrane plasmique sont les deux acteurs clefs de la transmission synaptique des cellules ciliées auditives

, L'expression de mini-Otof chez des souris Otof -/-nous a permis de montrer que la partie C

, C2-EF) est importante dans l'exocytose rapide mais que la forme entière à six domaines C2 reste nécessaire pour une transmission synaptique efficiente

L. Mini-otof, ont été un outil intéressant dans la mise en évidence d'une endocytose ultra-rapide, ayant lieu simultanément avec l'exocytose. Cette voie d'endocytose ultra-rapide (? ~ 10 ms) dynamine-dépendante que nous avons mise en évidence nous permettrait d'expliquer le maintien de l'homéostasie membranaire des synapses des CCI (Fig.18). De plus, nous pensons que l'endocytose ultra-rapide est également dépendante de l'otoferline, suite à l'absence de l'effet de l'inhibiteur de dynamine sur la réponse de capacité membranaire des CCI, moins efficaces dans la transmission synaptique que l'otoferline entière

, Les interactions potentielles entre l'otoferline, via les domaines C2-D ou C2-ABDF

. Ramakrishnan, Suite à l'expression in vivo des mini-Otof contenant les trois derniers domaines C2 en Cterminal (C2-DEF) dans les CCI, nous avons confirmé l'interaction directe ou indirecte de la partie Cterminale de l'otoferline avec les isoformes courtes Cav1.3S. En effet, la composante rapide de l'inactivation du courant calcique est absente chez les CCI Otof -/-et l'expression de ces mini-Otof a permis de restaurer partiellement cette inactivation rapide, caractéristique des Cav1.3S. Ces derniers, ne possédant pas de partie C-terminale régulatrice, présentent une inactivation rapide, propriété absente chez les Cav1.3L. Par édition génique, nous avons pu distinguer les rôles physiologiques de ces deux isoformes des canaux calciques. Nous montrons que les Cav1.3L sont indispensables à l'audition puisque la suppression par la technique du CRISPR-Cas9 de leur partie C-terminale, entraine une surdité sévère. Cette surdité s'explique au niveau synaptique par l'absence d'un recrutement efficace des vésicules à la ZA des CCI, tandis que l'exocytose rapide est maintenue. Une explication serait que les Cav1.3L, situés au voisinage des ZA et ne présentant pas d'inactivation, seraient alors requis pour une diffusion calcique intracellulaire large et profonde, Cav1.3 ont été établies à partir d'expériences biochimiques in vitro, vol.110, pp.1073-1081, 1997.

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