(Circulation. 1997;95:1260-1268.)
© 1997 American Heart Association, Inc.
Articles |
Norepinephrine Induces the raf-1 Kinase/Mitogen-Activated Protein Kinase Cascade Through Both 
1- and ß-Adrenoceptors
the Department of Medicine III (T.Y., I.K., Y.Z., S.K., I.S., Y.H., T.M., R.A., H.T., Y.Y.), University of Tokyo School of Medicine, and Health Service Center (T.Y.), University of Tokyo, Japan.
Correspondence to Issei Komuro, MD, PhD, Department of Medicine III, University of Tokyo School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky@umin.u-tokyo.ac.jp.
Background Although norepinephrine induces cardiac hypertrophy by activating protein kinase A and C through ß- and 
1-adrenoceptors, respectively, protein kinase A has been reported to inhibit cell growth in many other cell types.
Methods and Results To elucidate the molecular mechanism of norepinephrine-induced hypertrophic responses, we examined the effects of protein kinase A and protein kinase C on the activities of raf-1 kinase and mitogen-activated protein (MAP) kinases and on protein synthesis rates using cultured cardiomyocytes of neonatal rats. Norepinephrine-induced activation of MAP kinases was partially inhibited by either an 1-adrenoceptor blocker (prazosin) or a ß-adrenoceptor blocker (propranolol) and was completely abolished by both blockers. Both a ß-adrenoceptor agonist, isoproterenol, and an 1-adrenoceptor agonist, phenylephrine, increased the activities of raf-1 kinase and MAP kinases and phenylalanine incorporation into proteins. Furthermore, isoproterenol and phenylephrine synergistically activated these kinases and protein synthesis. Similar synergistic activation of MAP kinases was observed when other protein kinase A–activating agents such as forskolin, dibutyryl cAMP, and isobutylmethylxanthine were used with a protein kinase C–activating agent at the same time. Chelation of extracellular Ca2+ completely abolished isoproterenol- and phenylephrine-evoked MAP kinase activation.
Conclusions Norepinephrine activates the raf-1 kinase/MAP kinase cascade through both 1- and ß-adrenergic stimulation, and signaling pathways from the two receptors synergistically induce cardiomyocyte hypertrophy.
Key Words: hypertrophy • receptors, adrenergic, alpha • receptors, adrenergic, beta • kinase
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