title: Reduced rather than enhanced cholinergic airway constriction in mice with ablation of the large conductance Ca2+-activated K+ channel.
abstract: 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.
authors.affiliation: Pharmakologie und Toxikologie, Pharmazeutisches Institut, Universität Tübingen, Tübingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Sausbier
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhou
authors.forename: Caroline
authors.initials: C
authors.lastname: Beier
authors.forename: Ulrike
authors.initials: U
authors.lastname: Sausbier
authors.forename: Daniela
authors.initials: D
authors.lastname: Wolpers
authors.forename: Sylvi
authors.initials: S
authors.lastname: Maget
authors.forename: Christian
authors.initials: C
authors.lastname: Martin
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.forename: Anna-Rebekka
authors.initials: AR
authors.lastname: Ressmeyer
authors.forename: Harald
authors.initials: H
authors.lastname: Renz
authors.forename: Jens
authors.initials: J
authors.lastname: Schlossmann
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.forename: Winfried
authors.initials: W
authors.lastname: Neuhuber
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.forename: Michael
authors.initials: M
authors.lastname: Korth
authors.forename: Peter
authors.initials: P
authors.lastname: Ruth
mesh_terms: D000402:Airway Obstruction / Q000503:physiopathology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D006801:Humans; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000502:physiology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology; D011941:Receptors, Adrenergic / Q000502:physiology; D014132:Trachea / Q000187:drug effects / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D051036:Large-Conductance Calcium-Activated Potassium Channels; D011941:Receptors, Adrenergic; D016210:Methacholine Chloride; D002217:Carbachol