Received for publication July 25, 2006.
Revised July 28, 2006.
Accepted for publication July 28, 2006.

Is it GO or NO GO for SNO-modification-based therapies of CFTR trafficking? (Relates to article by Zaman, et al., FastForward 20 July 2006)

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, since both signaling mechanisms modulate a wide range of cellular functions. Zaman et al in this issue report on the capability of S-nitrosoglutathione (GSNO) to increase the expression, trafficking, and function of mutant and wildtype 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. At physiologic concentrations, Zaman et al in this issue show that 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.

Key words: Nitric oxide, Nitric oxide synthases, Ion transporters (SERCA, Na/K ATPase, CFTR), Glutathione S-transferases, Regulation - physiological, Glutathione, Oxidative stress/antioxidants, Reactive intermediates, Oxidative stress