Abstract
Compounds that enhance either the function or biosynthetic processing of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel may be of value in developing new treatments for cystic fibrosis (CF). Previous studies suggested that the herbal extract curcumin might affect the processing of a common CF mutant, CFTR-DeltaF508. Here, we tested the hypothesis that curcumin influences channel function. Curcumin increased CFTR channel activity in excised, inside-out membrane patches by reducing channel closed time and prolonging the time channels remained open. Stimulation was dose-dependent, reversible, and greater than that observed with genistein, another compound that stimulates CFTR. Curcumin-dependent stimulation required phosphorylated channels and the presence of ATP. We found that curcumin increased the activity of both wild-type and DeltaF508 channels. Adding curcumin also increased Cl(-) transport in differentiated non-CF airway epithelia but not in CF epithelia. These results suggest that curcumin may directly stimulate CFTR Cl(-) channels.
Highlights
Compounds that enhance either the function or biosynthetic processing of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl؊ channel may be of value in developing new treatments for cystic fibrosis (CF)
We added curcumin dissolved in Me2SO directly to the cytosolic bath solution, because when we applied it through a perfusion system it adsorbed to the tubing, and we observed no effect on current
We found that curcumin slowly increased ClϪ current in non-CF epithelia, but it failed to alter current in CF epithelia
Summary
Cells and Expression Systems—For patch clamp studies, wild-type and mutant CFTR were transiently expressed in HeLa cells using a hybrid vaccinia virus system as described previously [21]. Cultures of human airway epithelia were obtained from non-CF and CF bronchus (⌬F508/⌬F508) and cultured at the air-liquid interface as described previously [23]. Epithelia were used at least 14 days after seeding when they were well differentiated with a surface consisting of ciliated cells, goblet cells, and other non-ciliated cells [23]. These differentiated epithelia retain the functional properties of airway epithelia including transepithelial electrolyte transport
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