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. Ca²⁺stimulated CREB serine 133 phosphorylation is mediated by a Ca²⁺-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 Ca²⁺-activated gene expression.