Stimulation of alpha1A-adrenoceptors in Rat-1 cells inhibits extracellular signal-regulated kinase by activating p38 mitogen-activated protein kinase.
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.
Alexandrov
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A
Department of Medicine, University of Essen, 45122 Essen, Germany.
Keffel
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Goepel
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Michel
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MC
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism / Q000648:ultrastructure; D007527:Isoenzymes / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D013268:Stimulation, Chemical; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
C547713:ADRA1A protein, human; C547715:Adra1a protein, rat; D002273:Carcinogens; D019332:Endothelin-1; D007527:Isoenzymes; D018340:Receptors, Adrenergic, alpha-1; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate