Extracellular signal-regulated kinase 1/2 control Ca2+-independent force development in histamine-stimulated bovine tracheal smooth muscle

1 The role of extracellular signal-regulated kinase (ERK)-1 and ERK-2 in co ntrolling histamine-induced tone in bovine trachealis was investigated. PD 098059, an inhibitor of mitogen-activated protein kinase kinase (MKK)-1, ha d no effect on the histamine concentration-response relationship that descr ibed contraction. However, in the presence of EGTA, PD 098059 produced a pa rallel 5 fold rightwards shift of the histamine concentration-response curv e without reducing the maximum response. The Pz-adrenoceptor agonist, proca terol, also displaced the histamine-concentration response curve to the rig ht but the effect was much greater than that evoked by PD 098059, noncompet itive and seen in the absence and presence of EGTA. 2 A low basal level of pERK-1 and pERK-2 was always detected in untreated t rachealis, which was significantly higher in EGTA-treated tissues and inhib ited by PD 098059 and procaterol. Histamine markedly enhanced the phosphory lation of ERK-1 and ERK-2 by a mechanism that was also enhanced by EGTA and significantly attenuated by procaterol and PD 098059. 3 Neither cholera toxin nor Sp-8-Br-cAMPS mimicked the ability of procatero l to dephosphorylate ERK. Similarly, neither pertussis toxin (PTX) nor Rp-8 -Br-cAMPS, an inhibitor of cyclic AMP-dependent protein kinase (PKA), affec ted basal pERK levels or antagonized the inhibitory effect of procaterol. 4 These data implicate the MKK-1/ERK signalling cascade in Ca2+-independent , histamine-induced contraction of bovine trachealis. In addition, the abil ity of procaterol to dephosphorylate ERK in an Rp-8-Br-cAMPS- and PTX-insen sitive manner suggests that this may contribute to the anti-spasmogenic act ivity of beta (2)-adrenoceptor agonists by activating a novel PKA-independe nt pathway.