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Am J Physiol Cell Physiol 275: C171-C178, 1998;
0363-6143/98 $5.00
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Vol. 275, Issue 1, C171-C178, July 1998

Partial restoration of cAMP-stimulated CFTR chloride channel activity in Delta F508 cells by deoxyspergualin

Canwen Jiang1, Shaona L. Fang1, Yong-Fu Xiao2, Sean P. O'Connor1, Steven G. Nadler3, Des W. Lee4, Douglas M. Jefferson4, Johanne M. Kaplan1, Alan E. Smith1, and Seng H. Cheng1

1 Genzyme Corporation, Framingham 01701-9322; 2 Department of Medicine, Harvard Medical School, Boston 02215; 4 Tufts University School of Medicine, Department of Physiology, and New England Medical Center, Department of Pediatrics and Medicine, Boston, Massachusetts 02111; and 3 Bristol-Myers Squibb, Princeton, New Jersey 08540

Deletion of the codon encoding phenylalanine 508 (Delta F508) is the most common mutation in cystic fibrosis (CF) and results in a trafficking defect. Mutant Delta F508-CF transmembrane conductance regulator (CFTR) protein retains functional activity, but the nascent protein is recognized as abnormal and, in consequence, is retained in the endoplasmic reticulum (ER) and degraded. It has been proposed that this retention in the ER is mediated, at least in part, by the cellular chaperones heat shock protein (HSP) 70 and calnexin. We have investigated the ability of deoxyspergualin (DSG), a compound known to compete effectively for binding with HSP70 and HSP90, to promote trafficking of Delta F508-CFTR to the cell membrane. We show that DSG treatment of immortalized human CF epithelial cells (Delta F508) and cells expressing recombinant Delta F508-CFTR partially restored cAMP-stimulated CFTR Cl- channel activity at the plasma membrane. Although there are several possible explanations for these results, one simple interpretation is that DSG may have altered the interaction between Delta F508-CFTR and its associated chaperones. If this is correct, agents capable of altering the normal functioning of cellular chaperones may provide yet another means of restoring CFTR Cl- channel activity to CF subjects harboring this class of mutations.

cystic fibrosis; cellular chaperones; 6-methoxy-N-(3-sulfopropyl)quinolinium fluorescence; whole cell patch clamp


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