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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

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Submitted on July 25, 2005
Revised on November 11, 2005

SERCA Pump Inhibitors Do Not Correct Biosynthetic Arrest of {Delta}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 ({Delta}F508) accounts for nearly 70% of all mutations that occur in the cystic fibrosis transmembrane conductance regulator (CFTR). The {Delta}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 {Delta}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 {Delta}F508 CF mice. We investigated the effect of these compounds in human airway epithelial cells to determine if they could induce {Delta}F508-CFTR maturation, and Cl- secretion. We also used Baby Hamster Kidney cells, heterologously expressing {Delta}F508-CFTR, to determine if SERCA inhibitors could interfere with the interaction between calnexin and CFTR and thereby correct the {Delta}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 {Delta}F508 mouse in vivo, and ii) induce Cl- secretion in intestine (jejunum and distal colon) and the gallbladder of the {Delta}F508 CF mouse. We conclude that curcumin and thapsigargin failed to induce maturation of {Delta}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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