Regulation of gene expression in hippocampal neurons by distinct calcium signaling pathways

Calcium ions (Ca²⁺) act as an intracellular second messenger and can enter neurons through various ion channels. Influx of Ca²⁺ through distinct types of Ca²⁺ channels may differentially activate biochemical processes. N-Methyl-D-aspartate (NMDA) receptors and L-type Ca²⁺ channels, two major sites of Ca²⁺ entry into hippocampal neurons, were found to transmit signals to the nucleus and regulated gene transcription through two distinct Ca²⁺ signaling pathways. Activation of the multifunctional Ca²⁺-calmodulin-dependent protein kinase (CaM kinase) was evoked by stimulation of either NMDA receptors or L-type Ca²⁺ channels; however, activation of CaM kinase appeared to be critical only for propagating the L-type Ca²⁺ channel signal to the nucleus. Also, the NMDA receptor and L-type Ca²⁺ channel pathways activated transcription by means of different cis-acting regulatory elements in the c-fos promoter. These results indicate that Ca²⁺, depending on its mode of entry into neurons, can activate two distinct signaling pathways. Differential signal processing may provide a mechanism by which Ca²⁺ controls diverse cellular functions.