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Changes in the concentration of intracellular Ca2+ ([Ca2+]i) in response to various stimuli play a role in regulating numerous cellular processes, including the activation of gene expression. In neurons, the extraordinary diversity of the response to Ca2+ signaling depends on the location, intensity, and duration of the Ca2+ transient. Interestingly, Ca2+-dependent gene transcription appears to be sensitive both to increases in nuclear Ca2+, which occur after relatively intense stimuli, and to highly localized increases in Ca2+ near the sites of Ca2+ influx. Activation of intracellular signaling pathways by specific types of Ca2+ channels depends on localization of specific Ca2+ receptors close to the channel mouth. The dual regulation of signaling pathways by Ca2+ near channels and in the nucleus may permit neurons to precisely tailor transcriptional activation to specific types of electrical or chemical stimuli and at the same time ensure that only robust stimuli that generate nuclear Ca2+ elevations are converted into long-term changes in gene expression.