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.
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Abbreviations
- CaCC:
-
Ca2+-activated Cl− channel
- CF:
-
cystic fibrosis
- CFTR:
-
cystic fibrosis transmembrane conductance regulator
- 1-EBIO:
-
1-ethyl-2-benzimidazolinone
- Isc:
-
equivalent short circuit current
- Rte:
-
transepithelial resistance
- UTP:
-
uridine5′-triphosphate
- Vte:
-
transepithelial voltage
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Acknowledgements
The authors thank Dr. Laszig, ENT Clinic, University Hospital Freiburg and Dr. D. Calenborn, ENT Clinic Ludwigshafen, for their cooperation, and Dr. R. C. Boucher, Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina at Chapel Hill, for discussion and critical reading of this manuscript. We also thank Mrs. S. Hirtz for expert technical assistance.
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Supported by the Deutsche Forschungsgemeinschaft (DFG MA 2081/2-1 and KU 1228/1-1), the Zentrum Klinische Forschung 1 University of Freiburg (ZKF1, A2), the Mukoviszidose e.V., Cystic Fibrosis Australia, and the Australian Research Council (ARC-00/ARCS243).
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Mall, M., Gonska, T., Thomas, J. et al. Modulation of Ca2+-Activated Cl− Secretion by Basolateral K+ Channels in Human Normal and Cystic Fibrosis Airway Epithelia. Pediatr Res 53, 608–618 (2003). https://doi.org/10.1203/01.PDR.0000057204.51420.DC
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DOI: https://doi.org/10.1203/01.PDR.0000057204.51420.DC
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