Long-term adaptive changes in neurons following brief periods of neuronal activity are likely to involve changes in gene expression. The mechanisms of activity-dependent gene expression have been explored in central neurons and the neuronal cell line PC12. Calcium influx through either NMDA receptors or voltage-sensitive calcium channels leads to the rapid induction of a number of immediate-early genes including c-fos. Promoter analysis indicates that Ca2+ influx through different calcium channels activates distinct signaling pathways that either target the serum response element (SRE) or the calcium response element (CaRE) within the c-fos promoter. Transcription through the CaRE requires the induced phosphorylation of the cAMP response element binding protein (CREB) at Ser133. This site on CREB is also phosphorylated in the suprachiasmatic nucleus in vivo upon light stimulation. These observations suggest Ca2+ can regulate gene expression by multiple signaling pathways including one that involves the Ca(2+)-dependent phosphorylation of the transcription factor CREB.