MEK modulates force-fluctuation-induced relengthening of canine tracheal smooth muscle.
Tidal breathing, and especially deep breathing, is known to antagonise bronchoconstriction caused by airway smooth muscle (ASM) contraction; however, this bronchoprotective effect of breathing is impaired in asthma. Force fluctuations applied to contracted ASM in vitro cause it to relengthen, force-fluctuation-induced relengthening (FFIR). Given that breathing generates similar force fluctuations in ASM, FFIR represents a likely mechanism by which breathing antagonises bronchoconstriction. Thus it is of considerable interest to understand what modulates FFIR, and how ASM might be manipulated to exploit this phenomenon. It was demonstrated previously that p38 mitogen-activated protein kinase (MAPK) signalling regulates FFIR in ASM strips. Here, it was hypothesised that the MAPK kinase (MEK) signalling pathway also modulates FFIR. In order to test this hypothesis, changes in FFIR were measured in ASM treated with the MEK inhibitor, U0126 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene). Increasing concentrations of U0126 caused greater FFIR. U0126 reduced extracellular signal-regulated kinase 1/2 phosphorylation without affecting isotonic shortening or 20-kDa myosin light chain and p38 MAPK phosphorylation. However, increasing concentrations of U0126 progressively blunted phosphorylation of high-molecular-weight caldesmon (h-caldesmon), a downstream target of MEK. Thus changes in FFIR exhibited significant negative correlation with h-caldesmon phosphorylation. The present data demonstrate that FFIR is regulated through MEK signalling, and suggest that the role of MEK is mediated, in part, through caldesmon.
Dowell
M L
ML
Section of Pulmonary Medicine, Dept of Pediatrics, The University of Chicago, 5841 S. Maryland Avenue, MC4064, Chicago, IL 60637, USA. mdowell@peds.bsd.uchicago.edu
Lavoie
T L
TL
Lakser
O J
OJ
Dulin
N O
NO
Fredberg
J J
JJ
Gerthoffer
W T
WT
Seow
C Y
CY
Mitchell
R W
RW
Solway
J
J
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D047630:Depsipeptides / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction; D013990:Tidal Volume; D014018:Tissue Distribution; D014132:Trachea / Q000378:metabolism*
D002070:Butadienes; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D009570:Nitriles; C113580:U 0126; C057531:jasplakinolide; D020929:Mitogen-Activated Protein Kinase Kinases