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.