Abstract
The beta-adrenergic system is implicated in long-term synaptic plasticity in the CNS, a process that requires protein synthesis. To identify proteins that are translated in response to beta-adrenergic receptor stimulation and the pathways that regulate this process, we investigated the effects of isoproterenol on the translation of striatal-enriched protein tyrosine phosphatase (STEP) in both cortico-striatal slices and primary neuronal cultures. Isoproterenol stimulation induced a rapid dose-dependent increase in STEP expression. Anisomycin blocked the increase in STEP expression while actinomycin D had no effect, suggesting a translation-dependent mechanism. Isoproterenol-induced STEP translation required activation of beta1-receptors. Application of the MAPK/ERK kinase (MEK) inhibitor SL327 blocked both isoproterenol-induced activation of pERK and subsequent STEP translation. Inhibitors of PI3K (LY294002) or mTOR (rapamycin) also completely blocked STEP translation. These results suggest that co-activation of both the ERK and PI3K-Akt-mTOR pathways are required for STEP translation. As one of the substrates of STEP includes ERK itself, these results suggest that STEP is translated upon beta-adrenergic activation as part of a negative feedback mechanism.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic alpha-1 Receptor Agonists*
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Adrenergic beta-Agonists / pharmacology*
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Animals
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Blotting, Western
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Cells, Cultured
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Dose-Response Relationship, Drug
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Fluorescent Antibody Technique
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Immunohistochemistry
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Isoproterenol / pharmacology
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Male
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Mitogen-Activated Protein Kinase 1 / biosynthesis
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Mitogen-Activated Protein Kinase 3 / biosynthesis
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Neuronal Plasticity / drug effects
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Biosynthesis / drug effects
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Protein Kinases / biosynthesis
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Protein Kinases / genetics
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Protein Tyrosine Phosphatases, Non-Receptor / biosynthesis*
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Protein Tyrosine Phosphatases, Non-Receptor / genetics
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Proto-Oncogene Proteins c-akt / biosynthesis
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Proto-Oncogene Proteins c-akt / genetics
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Signal Transduction / physiology
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Subcellular Fractions / drug effects
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Subcellular Fractions / metabolism
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TOR Serine-Threonine Kinases
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Transcription, Genetic / drug effects
Substances
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Adrenergic alpha-1 Receptor Agonists
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Adrenergic beta-Agonists
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Protein Kinases
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mTOR protein, rat
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Protein Tyrosine Phosphatases, Non-Receptor
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Ptpn5 protein, rat
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Isoproterenol