Abstract
Effects of cAMP on insulin-stimulated mitogen-activated protein (MAP) kinase pathway were examined using rat hepatoma H4EII cells. MAP kinase was rapidly activated and reached a peak 3 min after the stimulation by insulin. Forskolin (1 microM) and 8(4-chlorophenylthio)cAMP (8-CPT-cAMP) (0.1 mM) inhibited the insulin-stimulated MAP kinase activity. Pretreatment of the cells with H-8 (50 microM), a cAMP-dependent protein kinase inhibitor, enhanced the insulin-stimulated MAP kinase activity and partially restored the inhibitory effect of cAMP. Furthermore, insulin-induced phosphorylation of MAP kinase was inhibited by 8-CPT-cAMP, and the inhibition was restored by H-8. 8-CPT-cAMP did not inhibit the autophosphorylation of insulin receptor. These data indicate that elevation of intracellular cAMP blocks the insulin-stimulated MAP kinase pathway downstream of insulin receptor.
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Animals
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Calcium / pharmacology
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors*
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Colforsin / pharmacology
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Cyclic AMP / analogs & derivatives
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Cyclic AMP / pharmacology*
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Enzyme Activation / drug effects
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Glycerophosphates / pharmacology
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Insulin / pharmacology*
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Isoquinolines / pharmacology
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Liver Neoplasms, Experimental / enzymology*
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Manganese / pharmacology
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Phosphorylation
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Piperazines / pharmacology
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Rats
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Receptor, Insulin / metabolism
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Sodium Fluoride / pharmacology
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Thionucleotides / pharmacology
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Tumor Cells, Cultured
Substances
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Glycerophosphates
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Insulin
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Isoquinolines
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Piperazines
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Thionucleotides
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Colforsin
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8-((4-chlorophenyl)thio)cyclic-3',5'-AMP
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Manganese
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide
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Sodium Fluoride
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Cyclic AMP
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Receptor, Insulin
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Calcium-Calmodulin-Dependent Protein Kinases
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Calcium
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beta-glycerophosphoric acid