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Reduced rather than enhanced cholinergic airway constriction in mice with ablation of the large conductance Ca²⁺-activated K⁺ channel

Matthias Sausbier^*, Xiao-Bo Zhou, Caroline Beier, Ulrike Sausbier^*, Daniela Wolpers^*, Sylvi Maget, Christian Martin, Alexander Dietrich, Anna-Rebekka Ressmeyer, Harald Renz^||, Jens Schlossmann^¶, Franz Hofmann^¶, Winfried Neuhuber^#, Thomas Gudermann, Stefan Uhlig^,**, Michael Korth^,1 and Peter Ruth^*

^* Pharmakologie und Toxikologie, Pharmazeutisches Institut, Universität Tübingen, Tübingen, Germany;

Institut für Pharmakologie für Pharmazeuten, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany;

Leibniz Zentrum für Medizin und Biowissenschaften, Borstel, Germany;

Institut für Pharmakologie und Toxikologie, Universität Marburg, Marburg, Germany;

^|| Institut für Klinische Chemie und Molekulare Diagnostik, Universität Marburg, Marburg, Germany;

^¶ Institut für Pharmakologie und Toxikologie, Technische Universität München, München, Germany;

^# Institut für Anatomie, Universität Erlangen-Nürnberg, Erlangen, Germany; and

^** Institut für Pharmakologie und Toxikologie, Rheinisch-Westfälische Technische Hochschule Aachen, Aachen, Germany

¹Correspondence: Institut für Pharmakologie für Pharmazeuten, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. E-mail: korth{at}uke.uni-hamburg.de

The unique voltage- and Ca²⁺-dependent K⁺ (BK) channel, prominently expressed in airway smooth muscle cells, has been suggested as an important effector in controlling airway contractility. Its deletion in mice depolarized resting membrane potential of tracheal cells, suggesting an increased open-probability of voltage-gated Ca²⁺ channels. While carbachol concentration-dependently increased the tonic tension of wild-type (WT) trachea, mutant trachea showed a different response with rapid tension development followed by phasic contractions superimposed on a tonic component. Tonic contractions were substantially more dependent on L-type Ca²⁺ current in mutant than in WT trachea, even though L-type Ca²⁺ channels were not up-regulated. In the absence of L-type Ca²⁺ current, half-maximal contraction of trachea was shifted from 0.51 to 1.7 µM. In agreement, cholinergic bronchoconstriction was reduced in mutant lung slices, isolated-perfused lungs and, most impressively, in mutant mice analyzed by body plethysmography. Furthermore, isoprenaline-mediated airway relaxation was enhanced in mutants. In-depth analysis of cAMP and cGMP signaling revealed up-regulation of the cGMP pathway in mutant tracheal muscle. Inhibition of cGMP kinase reestablished normal sensitivity toward carbachol, indicating that up-regulation of cGMP signaling counterbalances for BK channel ablation, pointing to a predominant role of BK channel in regulation of airway tone.—Sausbier, M., Zhou, X.-B., Beier, C., Sausbier, U., Wolpers, D., Maget, S., Martin, C., Dietrich, A., Ressmeyer, A.-R., Renz, H., Schlossmann, J., Hofmann, F., Neuhuber, W., Gudermann, T., Uhlig, S., Korth, M., Ruth, P. Reduced rather than enhanced cholinergic airway constriction in mice with ablation of the large conductance Ca²⁺-activated K⁺ channel.

Key Words: knockout mice • BK channel • airway contractility • cyclic GMP/PKG signaling • cholinergic agonists

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