Extracellular signal-regulated kinase 1/2 control Ca(2+)-independent force development in histamine-stimulated bovine tracheal smooth muscle.
The role of extracellular signal-regulated kinase (ERK)-1 and ERK-2 in controlling histamine-induced tone in bovine trachealis was investigated. PD 098059, an inhibitor of mitogen-activated protein kinase kinase (MKK)-1, had no effect on the histamine concentration-response relationship that described contraction. However, in the presence of EGTA, PD 098059 produced a parallel 5 fold rightwards shift of the histamine concentration-response curve without reducing the maximum response. The beta(2)-adrenoceptor agonist, procaterol, also displaced the histamine-concentration response curve to the right but the effect was much greater than that evoked by PD 098059, non-competitive and seen in the absence and presence of EGTA. A low basal level of pERK-1 and pERK-2 was always detected in untreated trachealis, which was significantly higher in EGTA-treated tissues and inhibited by PD 098059 and procaterol. Histamine markedly enhanced the phosphorylation of ERK-1 and ERK-2 by a mechanism that was also enhanced by EGTA and significantly attenuated by procaterol and PD 098059. Neither cholera toxin nor SP:-8-Br-cAMPS mimicked the ability of procaterol to dephosphorylate ERK. Similarly, neither pertussis toxin (PTX) nor RP:-8-Br-cAMPS, an inhibitor of cyclic AMP-dependent protein kinase (PKA), affected basal pERK levels or antagonized the inhibitory effect of procaterol. These data implicate the MKK-1/ERK signalling cascade in Ca(2+)-independent, histamine-induced contraction of bovine trachealis. In addition, the ability of procaterol to dephosphorylate ERK in an RP:-8-Br-cAMPS- and PTX-insensitive manner suggests that this may contribute to the anti-spasmogenic activity of beta(2)-adrenoceptor agonists by activating a novel PKA-independent pathway.
Koch
A
A
Thoracic Medicine, National Heart and Lung Institute, Imperial College School of Medicine, Dovehouse Street, London SW3 6LY.
Nasuhara
Y
Y
Barnes
P J
PJ
Lindsay
M A
MA
Giembycz
M A
MA
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002417:Cattle; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D005419:Flavonoids / Q000494:pharmacology; D006632:Histamine / Q000494:pharmacology*; D066298:In Vitro Techniques; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D010276:Parasympatholytics / Q000494:pharmacology; D037342:Pertussis Toxin; D010766:Phosphorylation; D014132:Trachea / Q000187:drug effects* / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D005419:Flavonoids; D010276:Parasympatholytics; D010566:Virulence Factors, Bordetella; D006632:Histamine; D000242:Cyclic AMP; D037342:Pertussis Toxin; D017868:Cyclic AMP-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium