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channels in human lung
epithelia: activation by arachidonic acid, amidation, and
acid-activated omeprazole
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0576
ClC-2 Cl
channels represent a potential target for
therapy in cystic fibrosis. Key questions regarding the feasibility of using ClC-2 as a therapeutic target are addressed in the present studies, including whether the channels are present in human lung epithelia and whether activators of the channel can be identified. Two
new mechanisms of activation of human recombinant ClC-2
Cl channels expressed in HEK-293 cells were identified:
amidation with glycine methyl ester catalyzed by
1-ethyl-3(3-dimethylaminopropyl) carbodiimide (EDC) and treatment with
acid-activated omeprazole. ClC-2 mRNA was detected by RT-PCR. Channel
function was assessed by measuring Cl currents by patch
clamp in the presence of a cAMP-dependent protein kinase (PKA)
inhibitor, myristoylated protein kinase inhibitor, to prevent
PKA-activated Cl currents. Calu-3, A549, and BEAS-2B cell
lines derived from different human lung epithelia contained ClC-2 mRNA,
and Cl currents were increased by amidation,
acid-activated omeprazole, and arachidonic acid. Similar results were
obtained with buccal cells from healthy individuals and cystic fibrosis
patients. The ClC-2 Cl channel is thus a potential target
for therapy in cystic fibrosis.
lung chloride channels; lung epithelia; 1-ethyl-3(3-dimethylaminopropyl) carbodiimide; pH-activated ion channels; water-soluble carbodiimides; Calu-3; A549; BEAS-2B; buccal cells
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