L-type voltage-sensitive Ca2+ channel activation regulates c-fos transcription at multiple levels.
A mechanism by which voltage-sensitive Ca2+ channel (VSCC) activation triggers c-fos transcription has been characterized. Ca2+ influx through VSCCs stimulates phosphorylation of the transcription factor cAMP response element-binding protein (CREB) on serine 133 leading to an increase in the formation of transcription complexes that can elongate through a transcription pause site within the c-fos gene. Ca(2+)-stimulated CREB serine 133 phosphorylation is mediated by a Ca(2+)-activated kinase and is not dependent on the cAMP-dependent protein kinase (PKA). While necessary for c-fos transcriptional induction following VSCC opening, CREB serine 133 phosphorylation is not sufficient for transcriptional activation. A second, PKA-dependent event is required. Following induction, c-fos transcription is rapidly down-regulated. Dephosphorylation of CREB serine 133 parallels and likely mediates the transcriptional shut-off event. These results suggest that the phosphorylation and dephosphorylation of CREB controls its ability to regulate transcription in membrane-depolarized cells and that multiple pathways contribute to Ca(2+)-activated gene expression.
Thompson
M A
MA
Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115.
Ginty
D D
DD
Bonni
A
A
Greenberg
M E
ME
D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D016762:Genes, fos; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D016716:PC12 Cells; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D015220:Calcium Channels; D017362:Cyclic AMP Response Element-Binding Protein; D009838:Oligodeoxyribonucleotides; D011494:Protein Kinases; D002118:Calcium