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. Hellson, Karl Delsseroth, Richard W. Tsien, Gerald R. Crabtree

Research output: Contribution to journalArticlepeer-review

437 Scopus citations

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 NFATc4/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 NFATc4, 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 I 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.

Original languageEnglish (US)
Pages (from-to)703-708
Number of pages6
JournalNature
Volume401
Issue number6754
DOIs
StatePublished - Oct 14 1999

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