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

Autor: Stefan Uhlig, Daniela Wolpers, Thomas Gudermann, Peter Ruth, Franz Hofmann, Xiaobo Zhou, Winfried Neuhuber, Harald Renz, Anna-Rebekka Ressmeyer, Ulrike Sausbier, Christian Martin, Michael Korth, Jens Schlossmann, Matthias Sausbier, Caroline Beier, Sylvi Maget, Alexander Dietrich
Rok vydání: 2006
Předmět:
Zdroj: The FASEB Journal. 21:812-822
ISSN: 1530-6860
0892-6638
DOI: 10.1096/fj.06-7167com
Popis: 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 microM. 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.
Databáze: OpenAIRE
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