Is it go or NO go for S-nitrosylation modification-based therapies of cystic fibrosis transmembrane regulator trafficking?

Pamela L. Zeitlin

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1155-1158
Number of pages4
JournalMolecular Pharmacology
Volume70
Issue number4
DOIs
StatePublished - 2006

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Cystic Fibrosis
Protein S
Therapeutics
S-Nitrosothiols
S-Nitrosoglutathione
Respiratory Mucosa
Chloride Channels
Guanylate Cyclase
Golgi Apparatus
Sulfhydryl Compounds
Nitric Oxide Synthase
Superoxides
Endoplasmic Reticulum
Epithelium
Salts
Molecular Weight
Phosphorylation
Water

ASJC Scopus subject areas

  • Pharmacology

Cite this

Is it go or NO go for S-nitrosylation modification-based therapies of cystic fibrosis transmembrane regulator trafficking? / Zeitlin, Pamela L.

In: Molecular Pharmacology, Vol. 70, No. 4, 2006, p. 1155-1158.

Research output: Contribution to journalArticle

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