SnapShot: Ca 2+-Dependent Transcription in Neurons

Abstract

Synaptic activity stimulates the influx of calcium ions into the postsynaptic neuron and thereby sets in motion a cascade of signaling events that lead to changes in gene expression. These changes in gene expression affect many aspects of nervous system development including dendritic morphogenesis, neuronal survival, and synapse development as well as the adaptive responses that underlie learning and memory in the mature nervous system. Mutations in components of the signal-ing pathways that participate in the process of experience-dependent brain development have been found to give rise to a variety of disorders of cognitive function including autism spectrum disorders.The initial contact between the axon and the dendrite during synapse development is mediated by cell surface-associated proteins on the pre- and postsynaptic membranes. For example, the binding of presynaptic β-neurexin to its postsynaptic receptor, Neuroligin1, leads to the recruitment of PSD-95 at nascent excitatory synapses. Ephrin/Eph signaling leads to the recruitment of additional proteins and the potentiation of NMDA receptor signaling. Release of the excitatory neurotrans-mitter glutamate from the presynaptic membrane and its binding to NMDA receptors and AMPA receptors on the postsynaptic membrane lead to the opening of these glutamate-gated ion channels. This is followed by membrane depolarization, opening of the L-type voltage-gated calcium ion channel (L-VSCC), and a rapid rise in calcium ions in the postsynaptic neuron as well as other local changes including protein recruitment and activation. Calcium entry through L-VSCCs leads to the recruitment of AKAP79/150, which then recruits PKA to the channel. PKA phosphorylates the calcium channel, thereby increasing its ability to allow calcium ions to flow into the cell. Calcium ion influx through L-VSCCs is sensed by calmodulin (CaM). Activated calmodulin initiates a cascade of events including stimulation of the guanine nucleotide exchange factor RasGRF, followed by activation of the Ras-MAPK signaling cascade. Calcium-activated calmodulin also activates the CaM kinase signaling pathway. Once activated these pathways trigger the phosphorylation and activation of a wide range of transcription factors such as CREB and NeuroD2. The phosphorylation of these transcription factors occurs in the nucleus and can be triggered by a cascade of events that begins at the site of calcium entry at the mouth of the calcium channel (that is, the Ras, Raf, MEK, ERK, RSK/MSK signaling pathway). Alternatively, channel activation can trigger an elevation of calcium ions directly in the nucleus that leads to activation of nuclear CaMKII by calcium/calmodulin, which in turn phosphorylates CREB and NeuroD2. In addition, dephosphorylation-dependent signaling through calcium/calmodulin activation of calcineurin leads to the activation of the transcripton factors NFAT and MEF2.Once activated and localized to the nucleus, calcium-activated transcription factors and modulators of transcription bind to the regulatory regions of activity-regulated genes to orchestrate finely tuned levels of gene expression. The most extensively studied activity-regulated gene is