Norepinephrine induces the raf-1 kinase/mitogen-activated protein kinase cascade through both alpha 1- and beta-adrenoceptors.
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.


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.
Yamazaki
T
T
Department of Medicine III, University of Tokyo School of Medicine, University of Tokyo, Japan.
Komuro
I
I
Zou
Y
Y
Kudoh
S
S
Shiojima
I
I
Hiroi
Y
Y
Mizuno
T
T
Aikawa
R
R
Takano
H
H
Yazaki
Y
Y
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D058668:Adrenergic alpha-1 Receptor Antagonists; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001692:Biological Transport / Q000187:drug effects; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D006332:Cardiomegaly; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D006321:Heart / Q000187:drug effects*; D007700:Kinetics; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism
D058668:Adrenergic alpha-1 Receptor Antagonists; D000596:Amino Acids; D011518:Proto-Oncogene Proteins; D018340:Receptors, Adrenergic, alpha-1; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D010656:Phenylephrine; D003994:Bucladesine; D011433:Propranolol; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine; D011224:Prazosin