Abstract
Enkephalin modulates striatal function, thereby affecting motor performance and addictive behaviors. The proenkephalin gene is also used as a model to study cyclic AMP-mediated gene expression in striatal neurons. The second messenger pathway leading to proenkephalin expression demonstrates how cyclic AMP pathways are synchronized with depolarization. We show that cyclic AMP-mediated regulation of the proenkephalin gene is dependent on the activity of L-type Ca2+ channels. Inhibition of L-type Ca2+ channels blocks forskolin-mediated induction of proenkephalin. The Ca2+-activated kinase, Ca2+/calmodulin kinase, as well as the cyclic AMP-activated kinase, protein kinase A (PKA), are both necessary for the induction of the proenkephalin promoter. Similarly, both kinases are needed for the L-type Ca2+ channel-mediated induction of proenkephalin. This synchronization of second messenger pathways provides a coincidence mechanism that gates proenkephalin synthesis in striatal neurons, ensuring that levels are increased only in the presence of activated PKA and depolarization.
Publication types
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Comparative Study
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / analogs & derivatives*
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / pharmacology
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Animals
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Antihypertensive Agents / pharmacology
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Calcium / metabolism*
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Calcium Channel Agonists / pharmacology
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Calcium Channel Blockers / pharmacology
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Carcinogens / pharmacology
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Cells, Cultured
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Colforsin / pharmacology
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism*
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Cyclic AMP / metabolism*
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Drug Interactions
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Embryo, Mammalian
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Enkephalins / biosynthesis*
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Enkephalins / genetics
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Developmental / drug effects*
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Humans
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Isoquinolines / pharmacology
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Neurons / drug effects
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Neurons / metabolism*
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Nifedipine / pharmacology
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Protein Precursors / biosynthesis*
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Protein Precursors / genetics
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Pyrroles / pharmacology
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Rats
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Rats, Sprague-Dawley
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Sulfonamides*
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Tetradecanoylphorbol Acetate / pharmacology
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Transcriptional Activation
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Transfection
Substances
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Antihypertensive Agents
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Calcium Channel Agonists
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Calcium Channel Blockers
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Carcinogens
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Enkephalins
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Enzyme Inhibitors
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Isoquinolines
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Protein Precursors
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Pyrroles
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Sulfonamides
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proenkephalin
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FPL 64176
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Colforsin
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KN 62
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1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
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Cyclic AMP
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Nifedipine
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N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
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Tetradecanoylphorbol Acetate
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Calcium