Fine tuning of calcium entry into neurons regulates adenosine 3',5'-monophosphate-dependent transcription by several distinct mechanisms.
Activation of both calcium and AMP-dependent regulatory pathways promotes survival of cerebellar neurons in vitro. Complex cellular programs such as survival must involve precise genetic responses. We show here, at the genomic level, that depolarization potentiates AMP-driven transcription of a variety of genes including the c-fos and c-jun proto-oncogenes, and the gene for somatostatin, proenkephalin and nerve growth factor. We used a reporter gene driven by the minimal AMP-responsive element (TGACGTCA) as a model system for studying this class of genes. In primary neurons, this reporter construct is co-activated in a synergistic manner by forskolin and KCl. We show that, in contrast to AMP, calcium-driven transcription does not require functional AMP-dependent protein kinase. Thus, when calcium and AMP levels are increased, these two second messengers stimulate transcription through different kinases which converge at the level of the AMP-responsive element. In addition, lower levels of intracellular free calcium can potentiate AMP-dependent transcription. This effect results from increased cyclic AMP accumulation and is strictly mediated by the AMP/AMP-dependent protein kinase pathway. In summary, low and high calcium concentrations potentiate AMP-dependent transcription via distinct mechanisms. Low calcium increases AMP production, whereas high calcium activates a non-cyclic AMP-dependent protein kinase, which in turn synergizes with AMP-activated transcription. These distinct mechanisms are likely to operate under specific physiological conditions within the neuronal network.
Barthel
F
F
Institut de Physiologie et de Chimie Biologique, Strasbourg, France.
Boutillier
A L
AL
Trouslard
J
J
Loeffler
J P
JP
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
D005576:Colforsin; D000242:Cyclic AMP; D011494:Protein Kinases; D002118:Calcium