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 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.

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Figure 1: Expression of NF-ATc4 and activation of NF-AT-dependent transcription by endogenous NF-AT proteins in the hippocampus.
Figure 2: Activation of NF-AT-dependent transcription by NMDA receptors and L-type Ca2+ channels.
Figure 3: Activity-dependent cytoplasmic-to-nuclear translocation of NF-ATc4 in hippocampal neurons.
Figure 4: GSK-3β blocks NF-AT-dependent transcription and promotes nuclear export of NF-ATc4.
Figure 5: NF-AT-dependent regulation of IP3R1.


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We thank T. Hoey for human NF-ATc4 cDNA, I. Bezprozvanny for the IP3R1 polyclonal antibody, D. Virshup for the casein kinase 1α expression construct, J. Healy for the MEKK expression construct and M. Karin for the JNK-1 expression construct. We also thank D. Wheeler, G. Pitt, J. H. Bayle and S. H. Park for helpful discussions. K.S. is a Stanford graduate fellow and a Howard Hughes Medical Institute predoctoral fellow. G.R.C. is an Investigator of the Howard Hughes Medical Institute. R.W.T is a McKnight Senior Investigator. This work was supported by grants from the NIH and the Mathels Charitable Trust.

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Correspondence to Gerald R. Crabtree.

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