D1 dopamine receptor activation of NFAT‐mediated striatal gene expression

Abstract

Exposure to drugs of abuse activates gene expression and protein synthesis that result in long-lasting adaptations in striatal signaling. Therefore, identification of the transcription factors that couple drug exposure to gene expression is of particular importance. Members of the nuclear factor of activated T-cells (NFATc) family of transcription factors have recently been implicated in shaping neuronal function throughout the rodent nervous system. Here we demonstrate that regulation of NFAT-mediated gene expression may also be a factor in drug-induced changes to striatal functioning. In cultured rat striatal neurons, stimulation of D1 dopamine receptors induces NFAT-dependent transcription through activation of L-type calcium channels. Additionally, the genes encoding inositol-1,4,5-trisphosphate receptor type 1 and glutamate receptor subunit 2 are regulated by striatal NFATc4 activity. Consistent with these in-vitro data, repeated exposure to cocaine triggers striatal NFATc4 nuclear translocation and the up-regulation of inositol-1,4,5-trisphosphate receptor type 1 and glutamate receptor subunit 2 gene expression in vivo, suggesting that cocaine-induced increases in gene expression may be partially mediated through activation of NFAT-dependent transcription. Collectively, these findings reveal a novel molecular pathway that may contribute to the enduring modifications in striatal functioning that occur following the administration of drugs of abuse.

Distinct Activation Properties of the Nuclear Factor of Activated T-cells (NFAT) Isoforms NFATc3 and NFATc4 in Neurons

“…One of the common signaling pathways recruited by neurotrophins involves activation of phosphatidylinositol 3-kinase (PI3K) and Akt kinase that, in turn, phosphorylates and inhibits GSK3␤ (80,81). Notably, it has been shown that NGF and brain-derived neurotrophic factor activate NFATc4 in neurons, although the specific role of the PI3K-Akt-dependent inhibition of GSK3␤ has not been tested in these studies (23,48,82).…”

“…Here, we describe the differential regulation of the two most commonly studied NFAT isoforms in neurons, NFATc3 and NFATc4 (5,6,20,21,23,(45)(46)(47)(48)(49)(50)(51). We find that although NFATc3 is rapidly dephosphorylated and translocates to the nucleus upon depolarization, NFATc4 remains phosphorylated and localized to the cytosol.…”

Store-Operated CRAC Channels Regulate Gene Expression and Proliferation in Neural Progenitor Cells

“…Therefore, we generated a conditional brainspecific KO of Orai1 by crossing Orai1 fl/fl mice to transgenic mice expressing Cre-recombinase under the nestin promoter. As described previously, nestin-Cre deleter mice are widely used to generate brain-specific deletion of target genes (Bates et al, 1999;Groszer et al, 2001). PCR analysis of genomic DNA isolated from various tissues showed deletion of Orai1 specifically in brain tissue derived from Orai1 fl/fl:Nes-Cre and Orai1 fl/ϩ:Nes-Cre mice, but not in the control mice (Fig.…”

“…NFAT-directed gene transcription regulates the expression of IP 3 Rs, GluRs, and pronociceptive genes in neurons (Groth and Mermelstein, 2003;Groth et al, 2007;Groth et al, 2008). Moreover, calcineurin-NFAT signaling is critical for neurotrophin-mediated axonal outgrowth (Nguyen and Di Giovanni, 2008) and Schwann-cell-mediated myelination of peripheral nerve fibers (Kao et al, 2009).…”

NFAT-3 Is a Transcriptional Repressor of the Growth-associated Protein 43 during Neuronal Maturation

“…Transgenic mice containing an NFAT reporter showed that NFAT transcriptional activity is highest in the brain (19,20), and NFAT-3 is specifically expressed in the spinal cord and the brain, with high levels found in the olfactory bulb, cerebellum, and certain regions of the cortex (21)(22)(23)(24). NFAT activity is important in neuronal growth and guidance during vertebrate development and appears to be downstream of neurotrophin and netrin signaling pathways (25)(26)(27).…”