title: F508del-CFTR increases intracellular Ca(2+) signaling that causes enhanced calcium-dependent Cl(-) conductance in cystic fibrosis.
abstract: In many cells, increase in intracellular calcium ([Ca(2+)](i)) activates a Ca(2+)-dependent chloride (Cl(-)) conductance (CaCC). CaCC is enhanced in cystic fibrosis (CF) epithelial cells lacking Cl(-) transport by the CF transmembrane conductance regulator (CFTR). Here, we show that in freshly isolated nasal epithelial cells of F508del-homozygous CF patients, expression of TMEM16A and bestrophin 1 was unchanged. However, calcium signaling was strongly enhanced after induction of expression of F508del-CFTR, which is unable to exit the endoplasmic reticulum (ER). Since receptor-mediated [Ca(2+)](i) increase is Cl(-) dependent, we suggested that F508del-CFTR may function as an ER chloride counter-ion channel for Ca(2+). This was confirmed by expression of the double mutant F508del/G551D-CFTR, which remained in the ER but had no effects on [Ca(2+)](i). Moreover, F508del-CFTR could serve as a scavenger for inositol-1,4,5-trisphosphate [IP3] receptor binding protein released with IP(3) (IRBIT). Our data may explain how ER-localized F508del-CFTR controls intracellular Ca(2+) signaling.
authors: Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors: Joana Raquel
authors: JR
authors: Martins
authors: Patthara
authors: P
authors: Kongsuphol
authors: Eva
authors: E
authors: Sammels
authors: Shehrazade
authors: S
authors: Dahimène
authors: Fadi
authors: F
authors: Aldehni
authors: Luka Alexander
authors: LA
authors: Clarke
authors: Rainer
authors: R
authors: Schreiber
authors: Humbert
authors: H
authors: de Smedt
authors: Margarida D
authors: MD
authors: Amaral
authors: Karl
authors: K
authors: Kunzelmann
mesh_terms: D043383:Adenosylhomocysteinase / Q000378:metabolism; D000818:Animals; D000075369:Anoctamin-1; D000075002:Bestrophins; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D002478:Cells, Cultured; D018118:Chloride Channels / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D006224:Cricetinae; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005136:Eye Proteins / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009297:Nasal Mucosa / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D017384:Sequence Deletion; D014982:Xenopus laevis / Q000378:metabolism
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; C113133:BEST1 protein, human; D000075002:Bestrophins; C505032:CFTR protein, human; D018118:Chloride Channels; D002712:Chlorides; D005136:Eye Proteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D043383:Adenosylhomocysteinase; C510392:IRBIT protein, mouse; D002118:Calcium