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Molecular Pharmacology Fast Forward
First published on July 28, 2006; DOI: 10.1124/mol.106.029207

0026-895X/06/7004-1155-1158$20.00
Mol Pharmacol 70:1155-1158, 2006

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Perspective

Is It Go or NO Go for S-Nitrosylation Modification-Based Therapies of Cystic Fibrosis Transmembrane Regulator Trafficking?

Pamela L. Zeitlin

Department of Pediatrics, Eudowood Division of Pediatric Respiratory Sciences, The Johns Hopkins School of Medicine, Baltimore, Maryland

Nitric-oxide synthases (NOS) are abundant in the respiratory epithelium and generate the NO radical, which can activate guanylate cyclase, react with superoxide, or modify proteins by S-nitrosylation (SNO) of Cys thiols. There is increasing appreciation that SNO modification is analogous to phosphorylation, because both signaling mechanisms modulate a wide range of cellular functions. Zaman et al. (p. 1435) in this issue report on the capability of S-nitrosoglutathione (GSNO) to increase the expression, trafficking, and function of mutant and wild-type cystic fibrosis transmembrane regulator (CFTR). The CFTR is a cAMP-regulated chloride channel that functions to regulate salt and water content in glands and ducts of secretory epithelia. GSNO is a low molecular weight SNO (S-nitrosothiol) formed during oxidation of NO. The authors use GSNO as a lead compound to restore mutant CFTR function. Earlier contradictory reports that GSNO decreased CFTR function by oxidative modification (glutathionylation) may now be explained by high concentrations of GSNO associated with decreased CFTR transcription and disruption of CFTR function. Zaman et al. show that at physiologic concentrations, GSNO and the constitutively active S-nitroso-glutathione diethyl ester stimulate CFTR transcription through SP1 and SP3 and promote normal trafficking. The mechanism behind rescue from the degradative pathway relies on increasing the expression of cysteine string proteins and SNO modification of chaperones involved in mediating CFTR transit through the endoplasmic reticulum and Golgi apparatus.

Received July 25, 2006; accepted July 28, 2006

Address correspondence to: Dr. Pamela Zeitlin, Park 316, 600 N. Wolfe St., Baltimore, MD 21287. E-mail. pzeitlin{at}jhmi.edu


Related articles in MolPharm:

S-Nitrosylating Agents: A Novel Class of Compounds That Increase Cystic Fibrosis Transmembrane Conductance Regulator Expression and Maturation in Epithelial Cells
Khalequz Zaman, Silvia Carraro, Joseph Doherty, Edward M. Henderson, Elizabeth Lendermon, Lei Liu, George Verghese, Molly Zigler, Mark Ross, Edward Park, Lisa A. Palmer, Allan Doctor, Jonathan S. Stamler, and Benjamin Gaston
MolPharm 2006 70: 1435-1442. [Abstract] [Full Text]  





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