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L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons
I A Graef1, P G Mermelstein, K Stankunas
1Department of Pathology, Howard Hughes Medical Institute, Stanford University Medical School, California 94305-5426, USA.
Abstract:
The molecular basis of learning and memory has been the object of several recent advances, which have focused attention on calcium-regulated pathways controlling transcription. One of the molecules implicated by pharmacological, biochemical and genetic approaches is the calcium/calmodulin-regulated phosphatase, calcineurin. In lymphocytes, calcineurin responds to specific calcium signals and regulates expression of several immediate early genes by controlling the nuclear import of the NF-ATc family of transcription factors. Here we show that NF-ATc4/NF-AT3 in hippocampal neurons can rapidly translocate from cytoplasm to nucleus and activate NF-AT-dependent transcription in response to electrical activity or potassium depolarization. The calcineurin-mediated translocation is critically dependent on calcium entry through L-type voltage-gated calcium channels. GSK-3 can phosphorylate NF-ATc4, promoting its export from the nucleus and antagonizing NF-ATc4-dependent transcription. Furthermore, we show that induction of the inositol 1,4,5-trisphosphate receptor type 1 is controlled by the calcium/calcineurin/NF-ATc pathway. This provides a new perspective on the function of calcineurin in the central nervous system and indicates that NF-AT-mediated gene expression may be involved in the induction of hippocampal synaptic plasticity and memory formation.
Insights
Calcineurin in hippocampal neurons regulates gene expression for memory formation. This calcium-regulated pathway involves NF-ATc4 nuclear translocation, crucial for synaptic plasticity.
Area of Science:
- Neuroscience
- Molecular Biology
- Cellular Signaling
Background:
- Learning and memory involve calcium-regulated gene transcription.
- Calcineurin, a calcium/calmodulin-regulated phosphatase, plays a role in cellular signaling.
- In lymphocytes, calcineurin controls NF-ATc transcription factor nuclear import.
Purpose of the Study:
- To investigate the role of calcineurin and NF-ATc4 in hippocampal neurons.
- To elucidate the molecular mechanisms underlying learning and memory formation.
Main Methods:
- Electrophysiological recordings and potassium depolarization to stimulate neurons.
- Calcium imaging to monitor calcium entry through L-type channels.
- Western blotting and immunofluorescence to assess protein translocation and phosphorylation.
Main Results:
- NF-ATc4 rapidly translocates to the nucleus in response to neuronal activity.
- Calcineurin-mediated NF-ATc4 translocation depends on L-type calcium channels.
- GSK-3 phosphorylation of NF-ATc4 inhibits its transcriptional activity.
- The calcium/calcineurin/NF-ATc pathway regulates inositol 1,4,5-trisphosphate receptor type 1 induction.
Conclusions:
- Calcineurin signaling is critical for NF-AT-mediated gene expression in the central nervous system.
- NF-AT-mediated gene expression is implicated in hippocampal synaptic plasticity and memory.
- This pathway offers new insights into the molecular basis of memory formation.