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

The molecular basis of learning and memory has been the object of several r ecent advances, which have focused attention on calcium-regulated pathways controlling transcription. One of the molecules implicated by pharmacologic al, biochemical and genetic approaches is the calcium/calmodulin-regulated phosphatase, calcineurin(1-5). In lymphocytes, calcineurin responds to spec ific calcium signals and regulates expression of several immediate early ge nes by controlling the nuclear import of the NF-ATc family of transcription factors(6-9). Here we show that NF-ATc4/NF-AT3 (ref. 10) in hippocampal ne urons can rapidly translocate from cytoplasm to nucleus and activate NF-AT- dependent transcription in response to electrical activity or potassium dep olarization. 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 antagonizi ng NF-ATc4-dependent transcription. Furthermore, we show that induction of the inositol 1,4,5-trisphosphate receptor type 1 is controlled by the calci um/calcineurin/NF-ATc pathway. This provides a new perspective on the funct ion of calcineurin in the central nervous system and indicates that NF-AT-m ediated gene expression may be involved in the induction of hippocampal syn aptic plasticity and memory formation.