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

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.

Interactions with PDZ Proteins Are Required for L-Type Calcium Channels to Activate cAMP Response Element-Binding Protein-Dependent Gene Expression

“…Media solutions contained 2 g/ml gentamicin (Invitrogen, Carlsbad, CA) to prevent bacterial growth. Cultured neurons were transfected 7-9 d in vitro (DIV) using a calcium phosphate-based technique (Graef et al, 1999). African Green Monkey kidney (COS-7) cells and human embryonic kidney (HEK)-293 cells were maintained in a DMEM-F12 solution (Life Technologies) containing 2 g/ml gentamicin.…”

“…This stimulus will activate not only CREB, but other transcription factors as well, including NFATc4 (Graef et al, 1999). For CREB, the stronger depolarization results in increased calcium entry through L-type channels and greater CREB activation.…”

“…6 B). AP5 was omitted from these experiments because NMDA receptors do not directly activate NFAT-dependent transcription under these conditions (Graef et al, 1999). In another test, nifedipine was used to block NFAT-dependent transcription mediated by endogenous synaptic activity.…”

Rocaglamide Derivatives Are Immunosuppressive Phytochemicals That Target NF-AT Activity in T Cells

“…The NF-AT family of proteins is activated by the calcium/calmodulin-dependent phosphatase calcineurin that dephosphorylates and promotes nuclear translocation of NF-AT (14,17). Glycogen synthase kinase-3 is the constitutive NF-AT kinase that induces rephosphorylation and, therefore, inactivation of NF-AT (29,30). Inactivation of NF-AT may also be regulated by the cellular MAPKs JNK and p38 that phosphorylate NF-AT and promote NF-AT nuclear export (19 -21).…”

Spatial and Intracellular Distribution of the Endogenous Calcineurin-Inhibitory Proteins, ZAKI-4, in Mouse Brain

“…Calcineurin is highly expressed in the brain and is thought to be involved in various important brain functions, particularly in memory and learning [10,12,16,30]. It also plays a role in brain ischemia [3,29] and neural cell apoptosis [1].…”