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 α1A-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.
Footnotes
- Received May 18, 1998.
- Accepted August 7, 1998.
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Send reprint requests to: Dr. Martin C. Michel, Nephrology Laboratory IG 1, Klinikum Essen, Hufelandstr. 55, 45122 Essen, Germany. E-mail: martin.michel{at}uni-essen.de
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This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (Goe 874/1–1) and the intramural grant program of the University of Essen (IFORES). A.A. was the recipient of a stipend from the Deutscher Akademischer Austauschdienst.
- The American Society for Pharmacology and Experimental Therapeutics
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