This Article Full Text Full Text (PDF) All Versions of this Article: 2005-0286OCv1 34/3/355    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Grubb, B. R. Articles by Boucher, R. C. Search for Related Content PubMed PubMed Citation Articles by Grubb, B. R. Articles by Boucher, R. C.

SERCA Pump Inhibitors Do Not Correct Biosynthetic Arrest of F508 CFTR in Cystic Fibrosis

Barbara R. Grubb^*, Sherif E. Gabriel^*, April Mengos, Martina Gentzsch, Scott H. Randell, Anna M. Van Heeckeren, Michael R. Knowles, Mitchell L. Drumm, John R. Riordan and Richard C. Boucher

University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Mayo Clinic College of Medicine, Scottsdale, Arizona; and Case Western Reserve University, Cleveland, Ohio

Correspondence and requests for reprints should be addressed to Barbara R. Grubb, Ph.D., Cystic Fibrosis/Pulmonary Research and Treatment Center, 7011 Thurston-Bowles Bldg., CB# 7248, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7248. 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. Sarcoplasmic/endoplasmic reticulum calcium (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 (1) induce Cl– secretion and reduce hyperabsorption of Na+ in the nasal epithelia of the F508 mouse in vivo, and (2) 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 electrophysiologic techniques in a variety of model systems ranging from cultured cells to in vivo studies.

Key Words: F508 CF mouse • CFTR trafficking • Cl^– channel • curcumin

This article has been cited by other articles:

				X.-b. Chang, A. Mengos, Y.-x. Hou, L. Cui, T. J. Jensen, A. Aleksandrov, J. R. Riordan, and M. Gentzsch Role of N-linked oligosaccharides in the biosynthetic processing of the cystic fibrosis membrane conductance regulator J. Cell Sci., September 1, 2008; 121(17): 2814 - 2823. [Abstract] [Full Text] [PDF]

				G. Vogt, J. Bustamante, A. Chapgier, J. Feinberg, S. Boisson Dupuis, C. Picard, N. Mahlaoui, L. Gineau, A. Alcais, C. Lamaze, et al. Complementation of a pathogenic IFNGR2 misfolding mutation with modifiers of N-glycosylation J. Exp. Med., August 4, 2008; 205(8): 1729 - 1737. [Abstract] [Full Text] [PDF]

				L. S. Ostedgaard, C. S. Rogers, Q. Dong, C. O. Randak, D. W. Vermeer, T. Rokhlina, P. H. Karp, and M. J. Welsh Processing and function of CFTR-{Delta}F508 are species-dependent PNAS, September 25, 2007; 104(39): 15370 - 15375. [Abstract] [Full Text] [PDF]

				C. Guilbault, Z. Saeed, G. P. Downey, and D. Radzioch Cystic Fibrosis Mouse Models Am. J. Respir. Cell Mol. Biol., January 1, 2007; 36(1): 1 - 7. [Abstract] [Full Text] [PDF]