L-type calcium channels and GSK-3 regulate the activity of NF-ATc4 in hippocampal neurons

Isabella A. Graef, Paul G. Mermelstein, Kryn Stankunas, Joel R. Neilson, Karl Deisseroth, Richard W. Tsien and Gerald R. Crabtree ()
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Isabella A. Graef: Howard Hughes Medical Institute
Paul G. Mermelstein: Beckman Center for Molecular and Genetic Medicine, Stanford University Medical School
Kryn Stankunas: Howard Hughes Medical Institute
Joel R. Neilson: Howard Hughes Medical Institute
Karl Deisseroth: Beckman Center for Molecular and Genetic Medicine, Stanford University Medical School
Richard W. Tsien: Beckman Center for Molecular and Genetic Medicine, Stanford University Medical School
Gerald R. Crabtree: Howard Hughes Medical Institute

Nature, 1999, vol. 401, issue 6754, 703-708

Abstract: 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, calcineurin1,2,3,4,5. 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 factors6,7,8,9. Here we show that NF-ATc4/NF-AT3 (ref. 10) 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.

Date: 1999
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DOI: 10.1038/44378

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