Regulation of Gene Expression in Hippocampal Neurons by Distinct Calcium Signaling Pathways

Calcium ions (Ca 2+ ) act as an intracellular second messenger and can enter neurons through various ion channels. Influx of Ca 2+ through distinct types of Ca 2+ channels may differentially activate biochemical processes. N -Methyl-D-aspartate (NMDA) receptors and L-type Ca 2+ channels, two major sites of Ca 2+ entry into hippocampal neurons, were found to transmit signals to the nucleus and regulated gene transcription through two distinct Ca 2+ signaling pathways. Activation of the multifunctional Ca 2+ -calmodulin-dependent protein kinase (CaM kinase) was evoked by stimulation of either NMDA receptors or L-type Ca 2+ channels; however, activation of CaM kinase appeared to be critical only for propagating the L-type Ca 2+ channel signal to the nucleus. Also, the NMDA receptor and L-type Ca 2+ channel pathways activated transcription by means of different cis-acting regulatory elements in the c- fos promoter. These results indicate that Ca 2+ , depending on its mode of entry into neurons, can activate two distinct signaling pathways. Differential signal processing may provide a mechanism by which Ca 2+ controls diverse cellular functions.