Abstract
Transient increases in the intracellular calcium concentration, which are associated with electrical activation of neurones, control synapse-to-nucleus communication. Calcium signals differ in time and space but it is unclear exactly how this translates into stimulus-specific gene expression. Analysis of transcription induced by calcium transients with defined durations revealed that the evoked genomic responses, unlike those following neurotrophin exposure, are not all-or-none but graded events. The CRE-binding protein CREB, its coactivator CREB-binding protein (CBP), and SRE-interacting transcriptional regulators are fast on-off switches: their activities are induced by short-lasting calcium signals, remain active for the duration of the signal and are rapidly shut-off after calcium concentrations have returned to basal levels. CREB is switched on by a fast, nuclear calmodulin (CaM) kinase-dependent mechanism that mediates CREB phosphorylation on serine 133 within 30 s of calcium entry. The second calcium-activated route to CREB involves the MAP kinase/extracellular signal-regulated kinase (ERK1/2) cascade. This pathway can be triggered by brief, 30-60 s calcium transients. ERK1/2 activity peaks several minutes after calcium entry and can outlast the calcium transient. The shut-off of CREB and ERK1/2 involves rapid dephosphorylation of their activator sites. These properties of transcription factors and their regulating kinases and phosphatases provide a mechanism through which the duration of calcium signals specifies the magnitude of the transcriptional response. The decoding of temporal features of calcium transients is likely to contribute to impulse-specific gene expression.
| Original language | English |
|---|---|
| Pages (from-to) | 849-58 |
| Number of pages | 10 |
| Journal | Journal of Neurochemistry |
| Volume | 79 |
| Issue number | 4 |
| Publication status | Published - 2001 |
Keywords
- Animals
- Brain-Derived Neurotrophic Factor
- CREB-Binding Protein
- Calcium Channel Agonists
- Calcium Channel Blockers
- Calcium Channels, L-Type
- Calcium Signaling
- Calcium-Calmodulin-Dependent Protein Kinases
- Cell Nucleus
- Cells, Cultured
- Cyclic AMP Response Element-Binding Protein
- Gene Expression
- Genes, Reporter
- Hippocampus
- MAP Kinase Signaling System
- Mice
- Neurons
- Nuclear Proteins
- Phosphorylation
- Pituitary Gland
- RNA, Messenger
- Serum Response Element
- Trans-Activators
- Transcription Factors
- Transcription, Genetic
- Transfection