Reduced rather than enhanced cholinergic airway constriction in mice with ablation of the large conductance Ca2+-activated K+ channel.
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.
Sausbier
Matthias
M
Pharmakologie und Toxikologie, Pharmazeutisches Institut, Universität Tübingen, Tübingen, Germany.
Zhou
Xiao-Bo
XB
Beier
Caroline
C
Sausbier
Ulrike
U
Wolpers
Daniela
D
Maget
Sylvi
S
Martin
Christian
C
Dietrich
Alexander
A
Ressmeyer
Anna-Rebekka
AR
Renz
Harald
H
Schlossmann
Jens
J
Hofmann
Franz
F
Neuhuber
Winfried
W
Gudermann
Thomas
T
Uhlig
Stefan
S
Korth
Michael
M
Ruth
Peter
P
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
D020746:Calcium Channels, L-Type; D051036:Large-Conductance Calcium-Activated Potassium Channels; D011941:Receptors, Adrenergic; D016210:Methacholine Chloride; D002217:Carbachol