Recruitment of the coactivator CBP by signal-regulated transcription factors and stimulation of CBP activity are key regulatory events in the induction of gene transcription following Ca²⁺ flux through ligand- and/or voltage-gated ion channels in hippocampal neurons. The mode of Ca²⁺ entry (L-type Ca²⁺ channels versus NMDA receptors) differentially controls the CBP recruitment step to CREB, providing a molecular basis for the observed Ca²⁺ channel type–dependent differences in gene expression. In contrast, activation of CBP is triggered irrespective of the route of Ca²⁺ entry, as is activation of c-Jun, that recruits CBP independently of phosphorylation at major regulatory c-Jun phosphorylation sites, serines 63 and 73. This control of CBP recruitment and activation is likely relevant to other CBP-interacting transcription factors and represents a general mechanism through which Ca²⁺ signals associated with electrical activity may regulate the expression of many genes.