Reduced rather than enhanced cholinergic airway constriction in mice with ablation of the large conductance Ca 2+ ‐activated K + channel

The unique voltage‐ and Ca 2+ ‐depen‐dent 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 Ca 2+ channels. While car‐bachol concentration‐dependently increased the tonic tension of wild‐type (WT) trachea, mutant trachea showed a different response with rapid tension devel‐opment followed by phasic contractions superimposed on a tonic component. Tonic contractions were sub‐stantially more dependent on L‐type Ca 2+ current in mutant than in WT trachea, even though L‐type Ca 2+ channels were not up‐regulated. In the absence of L‐type Ca 2+ 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‐depfh 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 Ca 2+ ‐activated K + channel. FASEB J. 21, 812–822 (2007)