title: SERCA and PMCA pumps contribute to the deregulation of Ca2+ homeostasis in human CF epithelial cells.
abstract: Cystic Fibrosis (CF) disease is caused by mutations in the CFTR gene (CF transmembrane conductance regulator). F508 deletion is the most represented mutation, and F508del-CFTR is absent of plasma membrane and accumulates into the endoplasmic reticulum (ER) compartment. Using specific Ca2+ genetics cameleon probes, we showed in the human bronchial CF epithelial cell line CFBE that ER Ca2+ concentration was strongly increased compared to non-CF (16HBE) cells, and normalized by the F508del-CFTR corrector agent, VX-809. We also showed that ER F508del-CFTR retention increases SERCA (Sarcoplasmic/Reticulum Ca2+ ATPase) pump activity whereas PMCA (Plasma Membrane Ca2+ ATPase) activities were reduced in these CF cells compared to corrected CF cells (VX-809) and non-CF cells. We are showing for the first time CFTR/SERCA and CFTR/PMCA interactions that are modulated in CF cells and could explain part of Ca2+ homeostasis deregulation due to mislocalization of F508del-CFTR. Using ER or mitochondria genetics Ca2+ probes, we are showing that ER Ca2+ content, mitochondrial Ca2+ uptake, SERCA and PMCA pump, activities are strongly affected by the localization of F508del-CFTR protein.
authors: NSERM U1078, Université Bretagne Occidentale, 22 Avenue Camille Desmoulins, 29200 Brest, France.
authors: Réginald
authors: R
authors: Philippe
authors: Department of Basic Neurosciences, 1, Rue Michel Servet, 1211 Geneva 4, Switzerland.
authors: Fabrice
authors: F
authors: Antigny
authors: NSERM U1078, Université Bretagne Occidentale, 22 Avenue Camille Desmoulins, 29200 Brest, France.
authors: Paul
authors: P
authors: Buscaglia
authors: Laboratoire Signalisation et Transport Ioniques Membranaires, Université Poitiers-CNRS Pole Biologie Santé, 1 rue George Bonnet, 86073 Poitiers Cedex, France.
authors: Caroline
authors: C
authors: Norez
authors: Laboratoire Signalisation et Transport Ioniques Membranaires, Université Poitiers-CNRS Pole Biologie Santé, 1 rue George Bonnet, 86073 Poitiers Cedex, France.
authors: Frédéric
authors: F
authors: Becq
authors: Cell Physiology and Metabolism University of Geneva Medical School, 1, Rue Michel Servet, 1211 Geneva 4, Switzerland.
authors: Maud
authors: M
authors: Frieden
authors: NSERM U1078, Université Bretagne Occidentale, 22 Avenue Camille Desmoulins, 29200 Brest, France. Electronic address: olivier.mignen@univ-brest.fr.
authors: Olivier
authors: O
authors: Mignen
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D001980:Bronchi / Q000473:pathology; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D052117:Benzodioxoles; C093349:cystic fibrosis transmembrane conductance regulator delta F508; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000255:Adenosine Triphosphate; D053499:Plasma Membrane Calcium-Transporting ATPases; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C569105:lumacaftor; D002118:Calcium
keywords: Calcium signaling; Cystic fibrosis; F508del-CFTR; PMCA; SERCA