Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia.
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.
Mall
Marcus
M
Department of Pediatrics and Adolescent Medicine, Albert Ludwigs University, Freiburg, Germany. mmall@med.unc.edu
Gonska
Tanja
T
Thomas
Jörg
J
Schreiber
Rainer
R
Seydewitz
Hans H
HH
Kuehr
Joachim
J
Brandis
Matthias
M
Kunzelmann
Karl
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D002712:Chlorides / Q000378:metabolism*; D002839:Chromans / Q000494:pharmacology; D003022:Clotrimazole / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; D008297:Male; D008875:Middle Aged; D009297:Nasal Mucosa / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D013449:Sulfonamides / Q000494:pharmacology; D014544:Uridine Triphosphate / Q000494:pharmacology
C505032:CFTR protein, human; D018118:Chloride Channels; D002712:Chlorides; D002839:Chromans; D006131:Growth Inhibitors; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D051656:KCNQ Potassium Channels; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; 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; D000242:Cyclic AMP; D003022:Clotrimazole; D002118:Calcium; D014544:Uridine Triphosphate