Article date: March 2004
By: Brice Marcet, Frédéric Becq, Caroline Norez, Patrick Delmas, Bernard Verrier in Volume 141, Issue 6, pages 905-914
Cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel is defective during cystic fibrosis (CF). Activators of the CFTR Cl− channel may be useful for therapy of CF. Here, we demonstrate that a range of general anesthetics like normal‐alkanols (n‐alkanols) and related compounds can stimulate the Cl− channel activity of wild‐type CFTR and delF508‐CFTR mutant.
The effects of n‐alkanols like octanol on CFTR activity were measured by iodide (125I) efflux and patch‐clamp techniques on three distinct cellular models: (1) CFTR‐expressing Chinese hamster ovary cells, (2) human airway Calu‐3 epithelial cells and (3) human airway JME/CF15 epithelial cells which express the delF508‐CFTR mutant.
Our data show for the first time that n‐alkanols activate both wild‐type CFTR and delF508‐CFTR mutant. Octanol stimulated 125I efflux in a dose‐dependent manner in CFTR‐expressing cells (wild‐type and delF508) but not in cell lines lacking CFTR. 125I efflux and Cl− currents induced by octanol were blocked by glibenclamide but insensitive to 4,4′‐diisothiocyanatostilbene‐2,2′‐disulfonic acid, as expected for a CFTR Cl− current.
CFTR activation by octanol was neither due to cell‐to‐cell uncoupling properties of octanol nor to an intracellular cAMP increase. CFTR activation by octanol requires phosphorylation by protein kinase‐A (PKA) since it was prevented by H‐89, a PKA inhibitor.
n‐Alkanols chain length was an important determinant for channel activation, with rank order of potencies: 1‐heptanol<1‐octanol<2‐octanol<1‐decanol. Our findings may be of valuable interest for developing novel therapeutic strategies for CF.
Cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel is defective during cystic fibrosis (CF). Activators of the CFTR Cl− channel may be useful for therapy of CF. Here, we demonstrate that a range of general anesthetics like normal‐alkanols (n‐alkanols) and related compounds can stimulate the Cl− channel activity of wild‐type CFTR and delF508‐CFTR mutant.
The effects of n‐alkanols like octanol on CFTR activity were measured by iodide (125I) efflux and patch‐clamp techniques on three distinct cellular models: (1) CFTR‐expressing Chinese hamster ovary cells, (2) human airway Calu‐3 epithelial cells and (3) human airway JME/CF15 epithelial cells which express the delF508‐CFTR mutant.
Our data show for the first time that n‐alkanols activate both wild‐type CFTR and delF508‐CFTR mutant. Octanol stimulated 125I efflux in a dose‐dependent manner in CFTR‐expressing cells (wild‐type and delF508) but not in cell lines lacking CFTR. 125I efflux and Cl− currents induced by octanol were blocked by glibenclamide but insensitive to 4,4′‐diisothiocyanatostilbene‐2,2′‐disulfonic acid, as expected for a CFTR Cl− current.
CFTR activation by octanol was neither due to cell‐to‐cell uncoupling properties of octanol nor to an intracellular cAMP increase. CFTR activation by octanol requires phosphorylation by protein kinase‐A (PKA) since it was prevented by H‐89, a PKA inhibitor.
n‐Alkanols chain length was an important determinant for channel activation, with rank order of potencies: 1‐heptanol<1‐octanol<2‐octanol<1‐decanol. Our findings may be of valuable interest for developing novel therapeutic strategies for CF.
British Journal of Pharmacology (2004) 141, 905–914. doi:10.1038/sj.bjp.0705684
DOI: 10.1038/sj.bjp.0705684
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