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J. Biol. Chem., Vol. 278, Issue 51, 51232-51242, December 19, 2003

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Organic Solutes Rescue the Functional Defect in F508 Cystic Fibrosis Transmembrane Conductance Regulator^*

Xue-Mei Zhang, Xi-Tao Wang, Hongwen Yue¶, Steve W. Leung, Patrick H. Thibodeau||, Philip J. Thomas||, and Sandra E. Guggino**

From the Department of Medicine and ^¶Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and the ^||Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75235

The most common defect in cystic fibrosis, deletion of phenylalanine from position 508 of the cystic fibrosis transmembrane conductance regulator (F508 CFTR), decreases the trafficking of this protein to the cell surface membrane. Previous studies have shown that low temperature and high concentrations of glycerol or trimethylamine N-oxide can partially counteract the processing defect of F508 CFTR. The present study investigates whether physiologically relevant concentrations of organic solutes, accumulated by cotransporter proteins, can rescue the misprocessing of F508 CFTR. Myoinositol alone or myoinositol, betaine, and taurine given sequentially increased the processing of core-glycosylated, endoplasmic reticulum-arrested F508 CFTR into the fully glycosylated form of CFTR in IB3 cells or NIH 3T3 cells stably expressing F508 CFTR. Pulse-chase experiments using transiently transfected COS7 cells demonstrated that organic solutes also increased the processing of the core-glycosylated form of green fluorescent protein-F508 CFTR. Moreover, the prolonged half-life of the complex-glycosylated form of GFP-F508 CFTR suggests that this treatment stabilized the mature form of the protein. In vitro studies of purified NBD1 stability and aggregation showed that myoinositol stabilized both the F508 and wild type CFTR and inhibited F508 misfolding. Most significantly, treatment of CF bronchial airway cells with these transportable organic solutes restores cAMP-stimulated single channel activity of both CFTR and outwardly rectifying chloride channel in the cell surface membrane and also restores a forskolin-stimulated macroscopic ³⁶Cl^- efflux. We conclude that organic solutes can repair CFTR functions by enhancing the processing of F508 CFTR to the plasma membrane by stabilizing the complex-glycosylated form of F508 CFTR.

Received for publication, August 15, 2003 , and in revised form, September 24, 2003.

^* This work was funded by the Cystic Fibrosis Foundation (to S. W. L.), Cystic Fibrosis Foundation Grant WANG_X99F0 (to X.-T. W.), Cystic Fibrosis Grant GUGGINO00GO (to S. E. G.), a grant from the Cystic Fibrosis Foundation Research Development Program (to W. B. Guggino), and National Institutes of Health Grant DK49835 (to P. J. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These two authors contributed equally to this work.

^** To whom correspondence should be addressed: Dept. of Medicine, The Johns Hopkins University School of Medicine, Rm. 929 Ross Bldg., 720 Rutland Ave., Baltimore, MD 21205. Tel.: 410-955-9690; Fax: 410-955-9677; E-mail: sguggino{at}jhmi.edu.

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