Stimulation of α_1A-Adrenoceptors in Rat-1 Cells Inhibits Extracellular Signal-Regulated Kinase by Activating p38 Mitogen-Activated Protein Kinase

Abstract

In Rat-1 fibroblasts, endothelin-1 and a protein kinase C-stimulating phorbol ester stimulated extracellular signal-regulated kinase (ERK), whereas phenylephrine, acting at stably transfected human alpha1A-adrenoceptors, inhibited basal and endothelin-1- and phorbol ester-stimulated ERK. On the other hand, phenylephrine stimulated p38 mitogen-activated protein kinase (MAPK). Anisomycin caused p38 activation and ERK inhibition quantitatively similar to those produced by phenylephrine. SB 203,580, an inhibitor of p38, significantly attenuated phenylephrine- and anisomycin-induced ERK inhibition. The ERK inhibition by phenylephrine was not affected by the cytosolic phospholipase A2 inhibitor arachidonyltrifluoromethyl ketone or the cyclooxygenase inhibitor indomethacin but was significantly attenuated by a combination of the phosphatase inhibitors Na3VO4 and okadaic acid. Neither SB 203,580 nor the phosphatase inhibitors significantly affected ERK inhibition by the adenylyl cyclase activator forskolin. We conclude that there is a previously unrecognized interaction between ERK and p38 MAPK, in which activation of p38 causes inhibition of ERK; this may at least partly involve MAPK phosphatases that inactivate ERK.

Mitogen-activated protein kinases in the heart

“…Thus, it could be expected that moderate and severe ischaemia have distinct effects on MAPK activation, but this has not been explored. Second, in contrast to yeast (Widmann et al 1999) mammalian MAPK are less compartmentalized and can cross-regulate each other (Alexandrov et al 1998;Daum et al 1998;Lim and Zaheer 1996;Ludwig et al 1998). Some data indicate that such cross-talk may also occur in cardiomyocytes (Aikawa et al 1997;Clerk et al 1998c).…”

“…Thus, in baboon smooth muscle cells pervanadate activated p38 and inhibited ERK; the inhibition of ERK was shown to occur at the level of MKK mek1 and to be sensitive to the p38 inhibitor SB 203,580 (Daum et al 1998). In Rat-1 fibroblasts stably transfected with human α 1A -adrenoceptors, receptor stimulation also activated p38 and inhibited basal and stimulated ERK; the ERK inhibition was mimicked by the p38 activator anisomycin, and the p38 inhibitor SB 203,580 attenuated ERK inhibition by anisomycin and α 1A -adrenoceptor stimulation (Alexandrov et al 1998). Moreover, the latter study demonstrated that phosphatase inhibitors could attenuate ERK inhibition by p38 stimulation, indicating that the inhibition may at least partly involve accelerated ERK inactivation by MAPK phosphatases.…”

Signalling pathways evoked by α1-adrenoceptors in human melanoma cells

“…Furthermore, PHE induced ERK inhibition, which, in these cells, was dependent on p38 activation. 23 Some reports suggest that MAPK participates in the mitogenic effects induced by 1 -adrenoceptor activation. 19,[24][25][26][27] In aorta cells, norepinephrine-promoted DNA synthesis and MAPK activation are dependent on phosphatidylinositol 3-kinase (PI3K).…”

A mitogen-activated protein kinase is involved in the inotropic but not chronotropic actions of adrenoceptor agonists and endothelin-1

“…Activation of the MAPK erk and MAPK p38 families by adrenoceptor agonists and endothelin-1 has repeatedly been shown in a variety of rat cardiac tissues and cells ). The MAPK p38 inhibitor SB203580, in a concentration which markedly suppresses MAPK p38 activation in cultured rat-1 cells (Alexandrov et al 1998), did not inhibit the inotropic and chronotropic responses to any of the agonists used in our study. Therefore, our data suggest that MAPK p38 is not involved in the mediation of cardiac inotropy or chronotropy.…”