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Norepinephrine induces the raf-1 kinase/mitogen-activated protein kinase cascade through both alpha 1- and
1Department of Medicine III, University of Tokyo School of Medicine, University of Tokyo, Japan.
Background:
Although norepinephrine induces cardiac hypertrophy by activating protein kinase A and C through beta- and alpha 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 alpha 1-adrenoceptor blocker (prazosin) or a beta-adrenoceptor blocker (propranolol) and was completely abolished by both blockers. Both a beta-adrenoceptor agonist, isoproterenol, and an alpha 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 isobutyl-methylxanthine 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 alpha 1- and beta-adrenergic stimulation, and signaling pathways from the two receptors synergistically induce cardiomyocyte hypertrophy.
Insights
Norepinephrine triggers cardiac hypertrophy via alpha 1 and beta-adrenergic stimulation, activating the raf-1 kinase/MAP kinase pathway. These synergistic signaling pathways promote cardiomyocyte growth.
Area of Science:
- Cardiovascular Biology
- Cell Signaling
- Molecular Cardiology
Background:
- Norepinephrine induces cardiac hypertrophy via protein kinase A (PKA) and C (PKC) activation through beta- and alpha 1-adrenoceptors.
- PKA paradoxically inhibits cell growth in many cell types, contrasting its role in cardiac hypertrophy.
Purpose of the Study:
- To elucidate the molecular mechanisms of norepinephrine-induced cardiac hypertrophy.
- Investigate the roles of PKA and PKC in activating raf-1 kinase and mitogen-activated protein (MAP) kinases.
- Determine the impact on protein synthesis rates in neonatal rat cardiomyocytes.
Main Methods:
- Cultured neonatal rat cardiomyocytes were used to study signaling pathways.
- Adrenergic receptor blockers (prazosin, propranolol) and agonists (isoproterenol, phenylephrine) were employed.
- Effects on raf-1 kinase, MAP kinases, and protein synthesis were measured, including extracellular Ca2+ chelation.
Main Results:
- Norepinephrine-induced MAP kinase activation was partially blocked by individual alpha 1 or beta-blockers and abolished by both.
- Beta- and alpha 1-adrenergic agonists synergistically activated raf-1 kinase, MAP kinases, and protein synthesis.
- Extracellular Ca2+ chelation completely inhibited agonist-evoked MAP kinase activation.
Conclusions:
- Norepinephrine activates the raf-1 kinase/MAP kinase cascade through both alpha 1- and beta-adrenergic stimulation.
- Synergistic signaling pathways from alpha 1- and beta-adrenergic receptors induce cardiomyocyte hypertrophy.
- Calcium ions play a critical role in mediating these hypertrophic responses.