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

TLDR

Calcium ions serve as intracellular second messengers that enter neurons through various ion channels, and the specific channel type can differentially activate downstream biochemical processes. In hippocampal neurons, NMDA receptors and L‑type Ca²⁺ channels trigger distinct nuclear signaling pathways that regulate gene transcription via separate Ca²⁺‑calmodulin‑dependent kinase activation and cis‑acting elements in the c‑fos promoter, illustrating that the mode of Ca²⁺ entry determines specific signaling outcomes.

Abstract

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.