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Rôle des phospholipases C dans la régulation de la sécrétion d'ions chlorure et de l'homéostasie calcique dans les cellules épithéliales bronchiques : intérêt dans la mucoviscidose

Abstract : Phospholipases C (PLC) are key enzymes involved in cellular transmission signals by membrane phospholipids hydrolysis and control, for instance, activities of proteins and ion channels. By producing DAG and IP3, PLC respectively activate protein kinase C and increase intracellular Ca2+ concentration, two pathways involved in the chloride channel CFTR (Cystic Fibrosis Transmembrane conductance Regulator) activity. Mutations on CFTR gene leads to the cystic fibrosis disease related to a loss of function and/or activity of CFTR. The aim of the thesis project is to study the extent to which PLC play a role in CFTR activity. Our results revealed an involvement of PLC in chloride secretion in bronchial epithelial cells depending on WT CFTR or temperature corrected F508del CFTR activity. In this way, we showed that PLC take part in maintaining chloride secretion over time via the activation of a non CFTR chloride channel. In addition, we identified PLCγ1 and PLCβ3 as two PLC required for maximal CFTR dependent chloride secretion, possibly by interacting with NHERF and SHANK2, both proteins involved in CFTR regulation. We also showed that PLCβ3 take part in calcium activated chloride channels (CaCC) activity. At last we showed a difference in the regulation of the TRPV6 calcium channel between bronchial epithelial cells expressing WT CFTR or F508del CFTR by a pathway involving PLC. To sum up, we showed that PLC take part in chloride secretion in bronchial epithelial cells. PLCβ3 in particular plays a role in different chloride channels including CFTR, CaCC and possibly a non CFTR chloride channel. These results could be managed in the future research to improve fluid secretion in context of cystic fibrosis.
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Chloé Grebert. Rôle des phospholipases C dans la régulation de la sécrétion d'ions chlorure et de l'homéostasie calcique dans les cellules épithéliales bronchiques : intérêt dans la mucoviscidose. Biochimie, Biologie Moléculaire. Université de Poitiers, 2019. Français. ⟨NNT : 2019POIT2301⟩. ⟨tel-02492604⟩

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