Freud-1: A neuronal calcium-regulated repressor of the 5-HT1A receptor gene

J Neurosci. 2003 Aug 13;23(19):7415-25. doi: 10.1523/JNEUROSCI.23-19-07415.2003.


Altered regulation of 5-HT1A receptors is implicated in mood disorders such as anxiety and major depression. To provide insight into its transcriptional regulation, we previously identified a novel DNA element [14 bp 5'-repressor element (FRE)] of the 5-HT1A receptor gene that mediates repression in neuronal and non-neuronal cells (Ou et al., 2000). We have now cloned a novel DNA binding protein [five' repressor element under dual repression binding protein-1 (Freud-1)] that binds to FRE to mediate repression of the 5-HT1A receptor or heterologous promoters. Freud-1 is evolutionarily conserved and contains two DM-14 basic repeats, a predicted helix-loop-helix DNA binding domain, and a protein kinase C conserved region 2 (C2)/calcium-dependent lipid binding (CalB) calcium/phospholipid binding domain. An intact CalB domain was required for Freud-1-mediated repression. In serotonergic raphe cells, overexpression of Freud-1 repressed the 5-HT1A promoter and decreased 5-HT1A receptor protein levels, whereas transfection of antisense to Freud-1 derepressed the 5-HT1A gene and increased 5-HT1A receptor protein expression. Calcium-dependent signaling blocked Freud-1-FRE binding and derepressed the 5-HT1A promoter. Treatment with inhibitors of calmodulin or CAM-dependent protein kinase reversed calcium-mediated inhibition of Freud-1. Freud-1 RNA and protein were present in raphe nuclei, hippocampus, cortex, and hypothalamus, and Freud-1 protein was colocalized with 5-HT1A receptors, suggesting its importance in regulating 5-HT1A receptors in vivo. Thus, Freud-1 represents a novel calcium-regulated repressor that negatively regulates basal 5-HT1A receptor expression in neurons and may play a role in the altered regulation of 5-HT1A receptors associated with anxiety or major depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / pharmacology
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Brain / metabolism
  • Calcium / pharmacology*
  • Cell Line
  • Cloning, Molecular
  • DNA-Binding Proteins / antagonists & inhibitors
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Gene Silencing* / drug effects
  • Molecular Sequence Data
  • Neurons / metabolism*
  • Protein Structure, Tertiary
  • RNA, Messenger / biosynthesis
  • Raphe Nuclei / metabolism
  • Rats
  • Receptors, Serotonin / biosynthesis
  • Receptors, Serotonin / genetics*
  • Receptors, Serotonin, 5-HT1
  • Repressor Proteins / antagonists & inhibitors
  • Repressor Proteins / genetics
  • Repressor Proteins / physiology*
  • Silencer Elements, Transcriptional


  • Cc2d1a protein, rat
  • DNA-Binding Proteins
  • RNA, Messenger
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Repressor Proteins
  • Adenosine Triphosphate
  • Calcium