Phenylephrine and noradrenaline (α-adrenergic agonism) or isoprenaline (β-adrenergic agonism) stimulated protein synthesis rates, increased the activity of the atrial natriuretic factor gene promoter and activated mitogen-activated protein kinase (MAPK). The EC50 for MAPK activation by noradrenaline was 2–4 μM and that for isoprenaline was 0.2–0.3 μM. Maximal activation of MAPK by isoprenaline was inhibited by the β-adrenergic antagonist, propranolol, whereas the activation by noradrenaline was inhibited by the α1-adrenergic antagonist, prazosin. FPLC on a Mono-Q column separated two peaks of MAPK (p42MAPK and p44MAPK) and two peaks of MAPK-activating activity (MEK) activated by isoprenaline or noradrenaline. Prolonged phorbol ester exposure partially down-regulated the activation of MAPK by noradrenaline but not by isoprenaline. This implies a role for protein kinase C in MAPK activation by noradrenaline but not isoprenaline. A role for cyclic AMP in activation of the MAPK pathway was eliminated when other agonists that elevate cyclic AMP in the cardiac myocyte did not activate MAPK. In contrast, MAPK was activated by exposure to ionomycin, Bay K8644 or thapsigargin that elevate intracellular Ca2+. Furthermore, depletion of extracellular Ca2+ concentrations with bis-(o-aminophenoxy)ethane-NNN´N´-tetra-acetic acid (BAPTA) or blocking of the L-type Ca2+ channel with nifepidine or verapamil inhibited the response to isoprenaline without inhibiting the responses to noradrenaline. We conclude that α- and β-adrenergic agonists can activate the MEK/MAPK pathway in the heart by different signalling pathways. Elevation of intracellular Ca2+ rather than cyclic AMP appears important in the activation of MAPK by isoprenaline in the cardiac myocyte.
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Research Article|
February 15 1996
Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy
Marie A. BOGOYEVITCH;
Marie A. BOGOYEVITCH
*
1Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.
*To whom correspondence should be addressed at: CRC Centre for Cell and Molecular Biology, Chester Beatty Laboratories, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, U.K.
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Monica B. ANDERSSON;
Monica B. ANDERSSON
1Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.
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Judith GILLESPIE-BROWN;
Judith GILLESPIE-BROWN
1Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.
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Angela CLERK;
Angela CLERK
1Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.
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Peter E. GLENNON;
Peter E. GLENNON
1Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.
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Stephen J. FULLER;
Stephen J. FULLER
1Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.
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Peter H. SUGDEN
Peter H. SUGDEN
1Cardiac Medicine, National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, Dovehouse Street, London SW3 6LY, U.K.
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Publisher: Portland Press Ltd
Received:
July 03 1995
Revision Received:
September 22 1995
Accepted:
October 10 1995
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London © 1996
1996
Biochem J (1996) 314 (1): 115–121.
Article history
Received:
July 03 1995
Revision Received:
September 22 1995
Accepted:
October 10 1995
Citation
Marie A. BOGOYEVITCH, Monica B. ANDERSSON, Judith GILLESPIE-BROWN, Angela CLERK, Peter E. GLENNON, Stephen J. FULLER, Peter H. SUGDEN; Adrenergic receptor stimulation of the mitogen-activated protein kinase cascade and cardiac hypertrophy. Biochem J 15 February 1996; 314 (1): 115–121. doi: https://doi.org/10.1042/bj3140115
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