PT - JOURNAL ARTICLE AU - Khalequz Zaman AU - Silvia Carraro AU - Joseph Doherty AU - Edward M. Henderson AU - Elizabeth Lendermon AU - Lei Liu AU - George Verghese AU - Molly Zigler AU - Mark Ross AU - Edward Park AU - Lisa A. Palmer AU - Allan Doctor AU - Jonathan S. Stamler AU - Benjamin Gaston TI - <em>S</em>-Nitrosylating Agents: A Novel Class of Compounds That Increase Cystic Fibrosis Transmembrane Conductance Regulator Expression and Maturation in Epithelial Cells AID - 10.1124/mol.106.023242 DP - 2006 Oct 01 TA - Molecular Pharmacology PG - 1435--1442 VI - 70 IP - 4 4099 - http://molpharm.aspetjournals.org/content/70/4/1435.short 4100 - http://molpharm.aspetjournals.org/content/70/4/1435.full SO - Mol Pharmacol2006 Oct 01; 70 AB - The endogenous bronchodilator, S-nitrosoglutathione (GSNO), increases expression, maturation, and function of both the wild-type and the ΔF508 mutant of the cystic fibrosis transmembrane conductance regulatory protein (CFTR). Though transcriptional mechanisms of action have been identified, GSNO seems also to have post-transcriptional effects on CFTR maturation. Here, we report that 1) GSNO is only one of a class of S-nitrosylating agents that, at low micromolar concentrations, increase ΔF508 and wild-type CFTR expression and maturation; 2) NO itself (at these concentrations) and 8-bromocyclic GMP are minimally active on CFTR; 3) a novel agent, S-nitrosoglutathione diethyl ester, bypasses the need for GSNO bioactivation by γ-glutamyl transpeptidase to increase CFTR maturation; 4) surprisingly, expression—but not S-nitrosylation—of cysteine string proteins (Csp) 1 and 2 is increased by GSNO; 5) the effect of GSNO to increase full maturation of wild-type CFTR is inhibited by Csp silencing (si)RNA; 6) proteins relevant to CFTR trafficking are SNO-modified, and SNO proteins traffic through the endoplasmic reticulum (ER) and Golgi after GSNO exposure; and 7) GSNO alters the interactions of ΔF508 CFTR with Csp and Hsc70 in the ER and Golgi. These data suggest that GSNO is one of a class of S-nitrosylating agents that act independently of the classic NO radical/cyclic GMP pathway to increase CFTR expression and maturation. They also suggest that the effect of GSNO is dependent on Csp and on intracellular SNO trafficking. We speculate that these data will be of relevance to the development of NO donor-based therapies for CF. The American Society for Pharmacology and Experimental Therapeutics