Maintaining low Ca2+ level in the endoplasmic reticulum restores abnormal endogenous F508del-CFTR trafficking in airway epithelial cells

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Caroline NorezClarisse Vandebrouck

Abstract

The most common mutation in cystic fibrosis, F508del, results in cystic fibrosis transmembrane conductance regulator protein (CFTR) that is retained in the endoplasmic reticulum (ER). Retention is dependent on chaperone proteins, many of which, like calnexin, require calcium for optimal activity. Here, we show that a limited and a maintained ER calcium level is sufficient to inhibit the F508del-CFTR/calnexin interaction and to restore the cAMP-dependent CFTR chloride transport, thus showing the correction of abnormal trafficking. We used Western blot analysis, iodide efflux and calcium measurement techniques applied to the human airway epithelial cystic fibrosis cell line CF15 (F508del/F508del). The inhibition of ER calcium pump, with thapsigargin, curcumin, 2,5-di(t-butyl)hydroquinone or cyclopiazonic acid, maintains a threshold levels of calcium that is correlated to the recovery of endogenous F508del-CFTR transport activity. In particular, cyclopiazonic acid restores a 2-aminoethyoxydiphenyl borate-sensitive F508del-CFTR trafficking with an EC50 of 915 nm. By contrast, the 1,4,5-trisphosphate or IP3 receptor activators, i.e., ATP and histamine, while transiently emptying the ER intracellular calcium store, did not affect the...Continue Reading

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Citations

Oct 27, 2010·Journal of Computer-aided Molecular Design·Ori KalidHanoch Senderowitz
Jun 17, 2011·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Frédéric BecqOlga Zegarra-Moran
Jul 24, 2008·Human Molecular Genetics·Anastasia SobolewskiNicholas W Morrell
Feb 21, 2007·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Peter J BentzenFlorian Lang
May 7, 2008·American Journal of Respiratory Cell and Molecular Biology·Rafal BartoszewskiZsuzsa Bebok
Jan 10, 2009·American Journal of Respiratory Cell and Molecular Biology·Caroline NorezFrédéric Becq
Mar 17, 2009·Respiratory Research·Mathilde RottnerM Carmen Martínez
Nov 1, 2008·Respiratory Research·Fabrice AntignyClarisse Vandebrouck
Jul 27, 2010·Expert Review of Proteomics·Mark J HendersonPamela L Zeitlin
Mar 3, 2009·Mitochondrion·Fabrice AntignyClarisse Vandebrouck
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Jun 19, 2007·Trends in Pharmacological Sciences·Margarida D Amaral, Karl Kunzelmann
Jun 13, 2013·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Laura VachelClarisse Vandebrouck
Feb 11, 2015·Biochimica Et Biophysica Acta·Réginald PhilippeOlivier Mignen
Sep 26, 2008·Journal of Cystic Fibrosis : Official Journal of the European Cystic Fibrosis Society·Maria Cristina DechecchiGiulio Cabrini
Jun 3, 2008·American Journal of Physiology. Lung Cellular and Molecular Physiology·Caroline NorezMarco Colombatti
Jan 31, 2008·The Journal of Pharmacology and Experimental Therapeutics·Caroline NorezFrédéric Becq
Apr 8, 2020·American Journal of Respiratory Cell and Molecular Biology·Benjamin J DunmoreNicholas W Morrell
May 14, 2020·International Journal of Molecular Sciences·Anna EspositoAnnalisa Guaragna
Mar 30, 2021·Frontiers in Pharmacology·Alessandro RimessiPaolo Pinton

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