title: Improvement of chloride transport defect by gonadotropin-releasing hormone (GnRH) in cystic fibrosis epithelial cells.
abstract: Cystic fibrosis (CF), the most common autosomal recessive disease in Caucasians, is due to mutations in the CFTR gene. F508del, the most frequent mutation in patients, impairs CFTR protein folding and biosynthesis. The F508del-CFTR protein is retained in the endoplasmic reticulum (ER) and its traffic to the plasma membrane is altered. Nevertheless, if it reaches the cell surface, it exhibits a Cl(-) channel function despite a short half-life. Pharmacological treatments may target the F508del-CFTR defect directly by binding to the mutant protein or indirectly by altering cellular proteostasis, and promote its plasma membrane targeting and stability. We previously showed that annexine A5 (AnxA5) directly binds to F508del-CFTR and, when overexpressed, promotes its membrane stability, leading to the restoration of some Cl(-) channel function in cells. Because Gonadotropin-Releasing Hormone (GnRH) increases AnxA5 expression in some cells, we tested it in CF cells. We showed that human epithelial cells express GnRH-receptors (GnRH-R) and that GnRH induces an AnxA5 overexpression and an increased Cl(-) channel function in F508del-CFTR cells, due to an increased stability of the protein in the membranes. Beside the numerous physiological implications of the GnRH-R expression in epithelial cells, we propose that a topical use of GnRH is a potential treatment in CF.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR1078, Brest, France ; Association Gaetan Saleun, Brest, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Benz
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR1078, Brest, France ; C.H.U. Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Hir
authors.affiliation: Institut de Physiologie et Biologie Cellulaires, Centre national de la recherche scientifique FRE 3511, Université de Poitiers, Poitiers, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Norez
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR1078, Brest, France ; Université de Bretagne Occidentale, Faculté de Médecine et des sciences de la santé, Brest, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Kerbiriou
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR1078, Brest, France ; Université de Bretagne Occidentale, Faculté de Médecine et des sciences de la santé, Brest, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Calvez
authors.affiliation: Institut de Physiologie et Biologie Cellulaires, Centre national de la recherche scientifique FRE 3511, Université de Poitiers, Poitiers, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Becq
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR1078, Brest, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Trouvé
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR1078, Brest, France ; C.H.U. Brest, Hôpital Morvan, Laboratoire de Génétique Moléculaire, Brest, France ; Université de Bretagne Occidentale, Faculté de Médecine et des sciences de la santé, Brest, France ; Etablissement Français du Sang - Bretagne, Brest, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
mesh_terms: D017304:Annexin A5 / Q000235:genetics / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology*; D006801:Humans; D009154:Mutation; D011966:Receptors, LHRH / Q000235:genetics / Q000378:metabolism
chemical_list: D017304:Annexin A5; C505032:CFTR protein, human; D002712:Chlorides; C484844:GNRHR protein, human; D011966:Receptors, LHRH; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007987:Gonadotropin-Releasing Hormone