Published ahead of print on November 11, 2005, doi:10.1165/rcmb.2005-0286OC
Am. J. Respir. Cell Mol. Biol., Volume 34, Number 3, March 2006, 355-363
A more recent version of this article appeared on March 1, 2006
Submitted on July 25, 2005
Revised on November 11, 2005
SERCA Pump Inhibitors Do Not Correct Biosynthetic Arrest of F508CFTR in Cystic Fibrosis
Barbara R Grubb1*, Sherif E Gabriel1, April Mengos2, Martina Gentzsch2, Scott H Randell1, Anna M Van Heeckeren3, Michael R Knowles1, Mitchell L Drumm3, John R Riordan2, and Richard C Boucher1
1 CF/Pulmonary Research and Treatment Center, The University of North Carolina, Chapel Hill, NC, USA,
2 Department of Cell Biology and Genetics, Mayo Clinic College of Medicine, Scottsdale, AZ, USA,
3 Department of Pediatric Pulmonology, Case Western Reserve University, Cleveland, OH, USA
* To whom correspondence should be addressed. E-mail: bgrubb{at}med.unc.edu.
Deletion of phenylalanine 508 ( F508) accounts for nearly 70% of all mutations that occur in the cystic fibrosis transmembrane conductance regulator (CFTR). The F508 mutation is a class II processing mutation that results in very little or no mature CFTR protein reaching the apical membrane and thus no cAMP-mediated Cl- conductance. Therapeutic strategies have been developed to enhance processing of the defective F508-CFTR molecule so that a functional cAMP-regulated Cl- channel targets to the apical membrane. SERCA inhibitors, curcumin and thapsigargin, have been reported to effectively correct the CF ion transport defects observed in the F508 CF mice. We investigated the effect of these compounds in human airway epithelial cells to determine if they could induce F508-CFTR maturation, and Cl- secretion. We also used Baby Hamster Kidney cells, heterologously expressing F508-CFTR, to determine if SERCA inhibitors could interfere with the interaction between calnexin and CFTR and thereby correct the F508-CFTR misfolding defect. Finally, at the whole animal level, we tested the ability of curcumin and thapsigargin to i) induce Cl- secretion and reduce hyperabsorption of Na+ in the nasal epithelia of the F508 mouse in vivo, and ii) induce Cl- secretion in intestine (jejunum and distal colon) and the gallbladder of the F508 CF mouse. We conclude that curcumin and thapsigargin failed to induce maturation of F508-CFTR, or induce Cl- secretion, as measured by biochemical and electrophysiological techniques in a variety of model systems ranging from cultured cells to in vivo studies.
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