We investigated the ability of phenylephrine (PE), an α-adrenergic agonist and promoter of hypertrophic growth in the ventricular myocyte, to activate the three best-characterized mitogen-activated protein kinase (MAPK) subfamilies, namely p38-MAPKs, SAPKs/JNKs (i.e. stress-activated protein kinases/c-Jun N-terminal kinases) and ERKs (extracellularly responsive kinases), in perfused contracting rat hearts. Perfusion of hearts with 100 µM PE caused a rapid (maximal at 10 min) 12-fold activation of two p38-MAPK isoforms, as measured by subsequent phosphorylation of a p38-MAPK substrate, recombinant MAPK-activated protein kinase 2 (MAPKAPK2). This activation coincided with phosphorylation of p38-MAPK. Endogenous MAPKAPK2 was activated 4–5-fold in these perfusions and this was inhibited completely by the p38-MAPK inhibitor, SB203580 (10 µM). Activation of p38-MAPK and MAPKAPK2 was also detected in non-contracting hearts perfused with PE, indicating that the effects were not dependent on the positive inotropic/chronotropic properties of the agonist. Although SAPKs/JNKs were also rapidly activated, the activation (2–3-fold) was less than that of p38-MAPK. The ERKs were activated by perfusion with PE and the activation was at least 50% of that seen with 1 µM PMA, the most powerful activator of the ERKs yet identified in cardiac myocytes. These results indicate that, in addition to the ERKs, two MAPK subfamilies, whose activation is more usually associated with cellular stresses, are activated by the Gq/11-protein-coupled receptor (Gq/11PCR) agonist, PE, in whole hearts. These data indicate that Gq/11PCR agonists activate multiple MAPK signalling pathways in the heart, all of which may contribute to the overall response (e.g. the development of the hypertrophic phenotype).
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Research Article|
June 01 1998
Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by the G-protein-coupled receptor agonist phenylephrine in the perfused rat heart
Antigone LAZOU;
Antigone LAZOU
*Laboratory of Animal Physiology, Department of Zoology, School of Biology, Aristotelian University of Thessaloniki, Thessaloniki 54006, Greece
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Peter H. SUGDEN;
Peter H. SUGDEN
1
†NHLI Division (Cardiac Medicine), Imperial College School of Medicine, Royal Brompton Campus, Dovehouse Street, London SW3 6LY, U.K.
1To whom correspondence should be addressed (e-mail p.sugden@ic.ac.uk).
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Angela CLERK
Angela CLERK
§Division of Biomedical Sciences, Imperial College School of Medicine, Charing Cross Campus, Fulham Palace Road, London W6 8RF, U.K.
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Publisher: Portland Press Ltd
Received:
January 14 1998
Revision Received:
February 25 1998
Accepted:
March 12 1998
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1998
1998
Biochem J (1998) 332 (2): 459–465.
Article history
Received:
January 14 1998
Revision Received:
February 25 1998
Accepted:
March 12 1998
Citation
Antigone LAZOU, Peter H. SUGDEN, Angela CLERK; Activation of mitogen-activated protein kinases (p38-MAPKs, SAPKs/JNKs and ERKs) by the G-protein-coupled receptor agonist phenylephrine in the perfused rat heart. Biochem J 1 June 1998; 332 (2): 459–465. doi: https://doi.org/10.1042/bj3320459
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