Am. J. Respir. Cell Mol. Biol., Volume 23, Number 3, September, 2000 283-289

Role of K_VLQT1 in Cyclic Adenosine Monophosphate-Mediated Cl Secretion in Human Airway Epithelia

Marcus Mall, Andreas Wissner, Rainer Schreiber, Joachim Kuehr, Hans H. Seydewitz, Matthias Brandis, Rainer Greger, and Karl Kunzelmann

Universitäts-Kinderklinik and Physiologisches Institut, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany; and Department of Physiology & Pharmacology, University of Queensland, Brisbane, Australia

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 µmol/liter), a specific inhibitor of K_VLQT1 K⁺ channels. Inhibition was increased after cAMP-dependent stimulation. Similar effects were obtained with Ba²⁺ (5 mmol/liter). In patch-clamp experiments with a human bronchial epithelial cell line, stimulation with forskolin (10 µmol/liter) simultaneously activated Cl and K⁺ conductance. The K⁺ conductance was reversibly inhibited by Ba²⁺ and 293B. Analysis of reverse-transcribed messenger RNA from non-CF and CF airways showed expression of human K_VLQT1. We conclude that the K⁺ channel K_VLQT1 is important in maintaining cAMP-dependent Cl secretion in human airways. Activation of K_VLQT1 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.

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