title: Role of K(V)LQT1 in cyclic adenosine monophosphate-mediated Cl(-) secretion in human airway epithelia.
abstract: Ion transport defects underlying cystic fibrosis (CF) lung disease are characterized by impaired cyclic adenosine monophosphate (cAMP)-dependent Cl(-) conductance. Activation of Cl(-) secretion in airways depends on simultaneous activation of luminal Cl(-) channels and basolateral K(+) channels. We determined the role of basolateral K(+) conductance in cAMP- dependent Cl(-) secretion in native human airway epithelium obtained from non-CF and CF patients. CF tissues showed typical alterations of short-circuit currents with enhanced amiloride-sensitive Na(+) conductance and defective cAMP-mediated Cl(-) conductance. In non-CF tissues, Cl(-) secretion was significantly inhibited by the chromanol 293B (10 micromol/liter), a specific inhibitor of K(V)LQT1 K(+) channels. Inhibition was increased after cAMP-dependent stimulation. Similar effects were obtained with Ba(2+) (5 mmol/liter). In patch-clamp experiments with a human bronchial epithelial cell line, stimulation with forskolin (10 micromol/liter) simultaneously activated Cl(-) and K(+) conductance. The K(+) conductance was reversibly inhibited by Ba(2+) and 293B. Analysis of reverse-transcribed messenger RNA from non-CF and CF airways showed expression of human K(V)LQT1. We conclude that the K(+) channel K(V)LQT1 is important in maintaining cAMP-dependent Cl(-) secretion in human airways. Activation of K(V)LQT1 in CF airways in parallel with stimulation of residual CF transmembrane conductance regulator Cl(-) channel activity or alternative Cl(-) channels could help to circumvent the secretory defect.
authors.affiliation: Universitäts-Kinderklinik and Physiologisches Institut, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mall
authors.forename: A
authors.initials: A
authors.lastname: Wissner
authors.forename: R
authors.initials: R
authors.lastname: Schreiber
authors.forename: J
authors.initials: J
authors.lastname: Kuehr
authors.forename: H H
authors.initials: HH
authors.lastname: Seydewitz
authors.forename: M
authors.initials: M
authors.lastname: Brandis
authors.forename: R
authors.initials: R
authors.lastname: Greger
authors.forename: K
authors.initials: K
authors.lastname: Kunzelmann
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000584:Amiloride / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D001980:Bronchi / Q000166:cytology / Q000378:metabolism*; D002461:Cell Line, Transformed; D002712:Chlorides / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D003550:Cystic Fibrosis / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D004232:Diuretics / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: C505032:CFTR protein, human; D002712:Chlorides; D002839:Chromans; D004232:Diuretics; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D010726:Phosphodiesterase Inhibitors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C103474:6-cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethylchromane; D005576:Colforsin; D000584:Amiloride; D000242:Cyclic AMP; D011188:Potassium; D015056:1-Methyl-3-isobutylxanthine