Calcium signaling plays an important role in gene expression. At the transcriptional level, this may underpin mammalian neuronal synaptic plasticity. Calcium influx into the postsynaptic neuron via: N-methyl-D-aspartate (NMDA) receptors activates small GTPase Rac1 and other Rac guanine nucleotide exchange factors, and stimulates calmodulin-dependent kinase kinase (CaMKK) and CaMKI; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors that are not impermeable to calcium ions, that is, those lacking the glutamate receptor-2 subunits, leads to activation of Ras guanine nucleotide-releasing factor proteins, which is coupled with activation of the mitogen-activated protein kinases/extracellular signal-regulated kinases signaling cascade; L-type voltage-gated calcium channels activates signaling pathways involving CaMKII, downstream responsive element antagonist modulator and distinct microdomains. Key members of these signaling cascades then translocate into the nucleus, where they alter the expression of genes involved in neuronal synaptic plasticity. At the post-transcriptional level, intracellular calcium level changes can change alternative splicing patterns; in the mammalian brain, alterations in calcium signaling via NMDA receptors is associated with exon silencing of the CI cassette of the NMDA R1 receptor (GRIN1) transcript by UAGG motifs in response to neuronal excitation. Regulation also occurs at the translational level; transglutaminase-2 (TG2) mediates calcium ion-regulated crosslinking of Y-box binding protein-1 (YB-1) translation-regulatory protein in TGFβ1-activated myofibroblasts; YB-1 binds smooth muscle α-actin mRNA and regulates its translational activity. Calcium signaling is also important in epigenetic regulation, for example in respect of changes in cytosine bases. Targeting calcium signaling may provide therapeutically useful options, for example to induce epigenetic reactivation of tumor suppressor genes in cancer patients.
Keywords: AMPA receptors; Alternative splicing patterns; Calcium signaling; Epigenetic regulation; Gene expression; Gene reactivation; L-type voltage-gated calcium channels; NMDA receptors; Transcription; Translation.