Calcium homeostasis is abnormal in cystic fibrosis airway epithelial cells but is normalized after rescue of F508del-CFTR.
Retention of F508del-CFTR proteins in the endoplasmic reticulum (ER) is dependent upon chaperone proteins, many of which require Ca(2+) for optimal activity. Here, we show in human tracheal gland CF-KM4 cells, that after correction of F508del-CFTR trafficking by miglustat (N-butyldeoxynojirimycin) or low temperature (27 degrees C), the Ca(2+) mobilization is decreased compared to uncorrected cells and becomes identical to the Ca(2+) response observed in non-CF MM39 cells. In CF-KM4 and human nasal epithelial CF15 cells, we also show that inhibiting vesicular trafficking by nocodazole prevents not only the rescue of F508del-CFTR but also the Ca(2+) mobilization decrease. Finally, experiments using the CFTR inhibitor CFTR(inh)-172 showed that the presence but not the channel activity of F508del-CFTR at the plasma membrane is required to decrease the Ca(2+) mobilization in corrected CF cells. These findings show that correction of the abnormal trafficking of F508del-CFTR proteins might have profound consequences on cellular homeostasis such as the control of intracellular Ca(2+) level.
Antigny
Fabrice
F
Institut de Physiologie et de Biologie Cellulaires, Université de Poitiers, CNRS UMR 6187, Poitiers Cedex, France.
Norez
Caroline
C
Becq
Frédéric
F
Vandebrouck
Clarisse
C
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000494:pharmacology; D001565:Benzoates / Q000494:pharmacology; D001896:Boron Compounds / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D003550:Cystic Fibrosis / Q000503:physiopathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology*; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D015739:Nocodazole / Q000494:pharmacology; D021381:Protein Transport / Q000502:physiology; D020545:Respiratory Mucosa / Q000502:physiology*; D017384:Sequence Deletion; D013696:Temperature; D053778:Thiazolidines / Q000494:pharmacology
C482900:3-((3-trifluoromethyl)phenyl)-5-((3-carboxyphenyl)methylene)-2-thioxo-4-thiazolidinone; D001565:Benzoates; D001896:Boron Compounds; C505032:CFTR protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D053778:Thiazolidines; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D017485:1-Deoxynojirimycin; D006632:Histamine; D000255:Adenosine Triphosphate; C059896:miglustat; C109986:2-aminoethoxydiphenyl borate; D015739:Nocodazole