Striatal proenkephalin gene induction: coordinated regulation by cyclic AMP and calcium pathways.
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.
Konradi
Christine
C
Laboratory of Neuroplasticity, McLean Hospital, Harvard Medical School, MRC215, 115 Mill St., Belmont, MA 02478, USA. konradi@mclean.harvard.edu
Macías
Wendy
W
Dudman
Joshua T
JT
Carlson
Richard R
RR
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004745:Enkephalins / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009543:Nifedipine / Q000494:pharmacology; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation; D014162:Transfection
D000959:Antihypertensive Agents; D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D002273:Carcinogens; D004745:Enkephalins; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D011498:Protein Precursors; D011758:Pyrroles; D013449:Sulfonamides; C029992:proenkephalin; C071658:FPL 64176; D005576:Colforsin; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000242:Cyclic AMP; D009543:Nifedipine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium