Abstract
Human airway epithelia express Ca2+-activated Cl- channels (CaCC) that are activated by extracellular nucleotides (ATP and UTP). CaCC is preserved and seems to be up-regulated in the airways of cystic fibrosis (CF) patients. In the present study, we examined the role of basolateral K+ channels in CaCC-mediated Cl- secretion in native nasal tissues from normal individuals and CF patients by measuring ion transport in perfused micro Ussing chambers. In the presence of amiloride, UTP-mediated peak secretory responses were increased in CF compared with normal nasal tissues. Activation of the cAMP pathway further increased CaCC-mediated secretion in CF but not in normal nasal mucosa. CaCC-dependent ion transport was inhibited by the chromanol 293B, an inhibitor of cAMP-activated hKvLQT1 K+ channels, and by clotrimazole, an inhibitor of Ca2+-activated hSK4 K+ channels. The K+ channel opener 1-ethyl-2-benzimidazolinone further increased CaCC-mediated Cl- secretion in normal and CF tissues. Expression of hSK4 as well as hCACC-2 and hCACC-3 but not hCACC-1 was demonstrated by reverse transcriptase PCR on native nasal tissues. We conclude that Ca2+-activated Cl- secretion in native human airway epithelia requires activation of Ca2+-dependent basolateral K+ channels (hSK4). Co-activation of hKvLQT1 improves CaCC-mediated Cl- secretion in native CF airway epithelia, and may have a therapeutic effect in the treatment of CF lung disease.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Adult
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Aged
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Biological Transport / drug effects
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Calcium / metabolism
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Child
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Child, Preschool
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Chloride Channels / genetics
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Chloride Channels / metabolism*
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Chlorides / metabolism*
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Chromans / pharmacology
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Clotrimazole / pharmacology
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Cyclic AMP / metabolism
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Cystic Fibrosis / metabolism*
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Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
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Female
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Gene Expression / physiology
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Growth Inhibitors / pharmacology
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Humans
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Intermediate-Conductance Calcium-Activated Potassium Channels
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KCNQ Potassium Channels
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KCNQ1 Potassium Channel
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Male
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Middle Aged
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Nasal Mucosa / metabolism*
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Potassium Channel Blockers / pharmacology
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Potassium Channels / genetics
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Potassium Channels / metabolism*
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Potassium Channels, Calcium-Activated*
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Potassium Channels, Voltage-Gated*
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Sulfonamides / pharmacology
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Uridine Triphosphate / pharmacology
Substances
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CFTR protein, human
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Chloride Channels
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Chlorides
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Chromans
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Growth Inhibitors
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Intermediate-Conductance Calcium-Activated Potassium Channels
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KCNN4 protein, human
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KCNQ Potassium Channels
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KCNQ1 Potassium Channel
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KCNQ1 protein, human
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Potassium Channel Blockers
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Potassium Channels
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Potassium Channels, Calcium-Activated
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Potassium Channels, Voltage-Gated
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Sulfonamides
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Cystic Fibrosis Transmembrane Conductance Regulator
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6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane
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Cyclic AMP
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Clotrimazole
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Calcium
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Uridine Triphosphate