title: Function and regulation of TRPM7, as well as intracellular magnesium content, are altered in cells expressing ΔF508-CFTR and G551D-CFTR.
abstract: Cystic fibrosis (CF), one of the most common fatal hereditary disorders, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene product is a multidomain adenosine triphosphate-binding cassette (ABC) protein that functions as a chloride (Cl(-)) channel that is regulated by intracellular magnesium [Mg(2+)]i. The most common mutations in CFTR are a deletion of a phenylalanine residue at position 508 (ΔF508-CFTR, 70-80 % of CF phenotypes) and a Gly551Asp substitution (G551D-CFTR, 4-5 % of alleles), which lead to decreased or almost abolished Cl(-) channel function, respectively. Magnesium ions have to be finely regulated within cells for optimal expression and function of CFTR. Therefore, the melastatin-like transient receptor potential cation channel, subfamily M, member 7 (TRPM7), which is responsible for Mg(2+) entry, was studies and [Mg(2+)]i measured in cells stably expressing wildtype CFTR, and two mutant proteins (ΔF508-CFTR and G551D-CFTR). This study shows for the first time that [Mg(2+)]i is decreased in cells expressing ΔF508-CFTR and G551D-CFTR mutated proteins. It was also observed that the expression of the TRPM7 protein is increased; however, membrane localization was altered for both ΔF508del-CFTR and G551D-CFTR. Furthermore, both the function and regulation of the TRPM7 channel regarding Mg(2+) is decreased in the cells expressing the mutated CFTR. Ca(2+) influx via TRPM7 were also modified in cells expressing a mutated CFTR. Therefore, there appears to be a direct involvement of TRPM7 in CF physiopathology. Finally, we propose that the TRPM7 activator Naltriben is a new potentiator for G551D-CFTR as the function of this mutant increases upon activation of TRPM7 by Naltriben.
authors.affiliation: Inserm, UMR1078, 46, rue Félix le Dantec, CS 51819, 29218, Brest Cedex 2, France.|Faculté de Médecine et des sciences de la santé, Université de Bretagne Occidentale, Brest, 29200, France.
authors.forename: F
authors.initials: F
authors.lastname: Huguet
authors.affiliation: Inserm, UMR1078, 46, rue Félix le Dantec, CS 51819, 29218, Brest Cedex 2, France.|Faculté de Médecine et des sciences de la santé, Université de Bretagne Occidentale, Brest, 29200, France.|Association G. Saleun, Brest, 29218, France.
authors.forename: M L
authors.initials: ML
authors.lastname: Calvez
authors.affiliation: Inserm, UMR1078, 46, rue Félix le Dantec, CS 51819, 29218, Brest Cedex 2, France.|Association G. Saleun, Brest, 29218, France.
authors.forename: N
authors.initials: N
authors.lastname: Benz
authors.affiliation: Inserm, UMR1078, 46, rue Félix le Dantec, CS 51819, 29218, Brest Cedex 2, France.|Laboratoire de Génétique Moléculaire, Hôpital Morvan, C.H.U. Brest, Brest, 29200, France.
authors.forename: S
authors.initials: S
authors.lastname: Le Hir
authors.affiliation: Inserm, UMR1078, 46, rue Félix le Dantec, CS 51819, 29218, Brest Cedex 2, France.|Faculté de Médecine et des sciences de la santé, Université de Bretagne Occidentale, Brest, 29200, France.
authors.forename: O
authors.initials: O
authors.lastname: Mignen
authors.affiliation: Inserm, UMR1078, 46, rue Félix le Dantec, CS 51819, 29218, Brest Cedex 2, France.|Faculté de Médecine et des sciences de la santé, Université de Bretagne Occidentale, Brest, 29200, France.
authors.forename: P
authors.initials: P
authors.lastname: Buscaglia
authors.affiliation: Laboratory of Marine Biological Chemistry, Department of Natural Sciences, Hawaii Pacific University, Kaneohe, HI, 96744, USA.
authors.forename: F D
authors.initials: FD
authors.lastname: Horgen
authors.affiliation: Inserm, UMR1078, 46, rue Félix le Dantec, CS 51819, 29218, Brest Cedex 2, France. claude.ferec@univ-brest.fr.|Faculté de Médecine et des sciences de la santé, Université de Bretagne Occidentale, Brest, 29200, France. claude.ferec@univ-brest.fr.|Laboratoire de Génétique Moléculaire, Hôpital Morvan, C.H.U. Brest, Brest, 29200, France. claude.ferec@univ-brest.fr.|Etablissement Français du Sang - Bretagne, Brest, 29200, France. claude.ferec@univ-brest.fr.
authors.forename: C
authors.initials: C
authors.lastname: Férec
authors.affiliation: Inserm, UMR1078, 46, rue Félix le Dantec, CS 51819, 29218, Brest Cedex 2, France.|Faculté de Médecine et des sciences de la santé, Université de Bretagne Occidentale, Brest, 29200, France.
authors.forename: M
authors.initials: M
authors.lastname: Kerbiriou
authors.affiliation: Inserm, UMR1078, 46, rue Félix le Dantec, CS 51819, 29218, Brest Cedex 2, France. pascal.trouve@univ-brest.fr.
authors.forename: P
authors.initials: P
authors.lastname: Trouvé
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000032:analysis; D018118:Chloride Channels / Q000378:metabolism; D000081007:Cymenes; D003550:Cystic Fibrosis / Q000235:genetics / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D016257:Fura-2 / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008274:Magnesium / Q000032:analysis* / Q000737:chemistry; D039821:Monoterpenes / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D060066:Protein Interaction Maps / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018118:Chloride Channels; D000081007:Cymenes; D039821:Monoterpenes; D012333:RNA, Messenger; D050053:TRPM Cation Channels; C093349:cystic fibrosis transmembrane conductance regulator delta F508; C068868:naltrindole benzofuran; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D009271:Naltrexone; D000255:Adenosine Triphosphate; C073316:carvacrol; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D008274:Magnesium; D002118:Calcium; D016257:Fura-2
keywords: CFTR; Cystic fibrosis; G551D-CFTR; Naltriben; TRPM7; ΔF508-CFTR