Role of KvLQT1 in cyclic adenosine monophosphate-mediated Cl- secretion in human airway epithelia

Ion transport defects underlying cystic fibrosis (CF) lung disease are characterized by impaired cyclic adenosine monophosphate (cAMP)-dependent CI- conductance. Activation of CI- secretion in airways depends on simultaneous activation of luminal CI- channels and basolateral K+ channels. We determined the role of basolateral K+ conductance in cAMP-dependent CI- 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 CI- conductance. In non-CF tissues, CI- secretion was significantly inhibited by the chromanol 293B (10 mu mol/liter), a specific inhibitor of K(V)LQT1 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 mu mol/liter) simultaneously activated CI- 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(V)LQT1, We conclude that the K+ channel K(V)LQT1 is important in maintaining cAMP-dependent CI- secretion in human airways. Activation of KVLQT1 in CF airways in parallel with stimulation of residual CF transmembrane conductance regulator CI- channel activity or alternative CI- channels could help to circumvent the secretory defect.