Par-4 links dopamine signaling and depression

Cell. 2005 Jul 29;122(2):275-87. doi: 10.1016/j.cell.2005.05.031.


Prostate apoptosis response 4 (Par-4) is a leucine zipper containing protein that plays a role in apoptosis. Although Par-4 is expressed in neurons, its physiological role in the nervous system is unknown. Here we identify Par-4 as a regulatory component in dopamine signaling. Par-4 directly interacts with the dopamine D2 receptor (D2DR) via the calmodulin binding motif in the third cytoplasmic loop. Calmodulin can effectively compete with Par-4 binding in a Ca2+-dependent manner, providing a route for Ca2+-mediated downregulation of D2DR efficacy. To examine the importance of the Par-4/D2DR interaction in dopamine signaling in vivo, we used a mutant mouse lacking the D2DR interaction domain of Par-4, Par-4DeltaLZ. Primary neurons from Par-4DeltaLZ embryos exhibit an enhanced dopamine-cAMP-CREB signaling pathway, indicating an impairment in dopamine signaling in these cells. Remarkably, Par-4DeltaLZ mice display significantly increased depression-like behaviors. Collectively, these results provide evidence that Par-4 constitutes a molecular link between impaired dopamine signaling and depression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Animals
  • Apoptosis Regulatory Proteins
  • Calcium / metabolism
  • Calmodulin / metabolism
  • Cells, Cultured
  • Corpus Striatum / metabolism
  • Cyclic AMP / physiology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Depression / metabolism*
  • Depression / physiopathology
  • Dopamine / metabolism*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Mice
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Mutation
  • Neurons / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Dopamine D2 / physiology*
  • Signal Transduction / physiology*
  • Up-Regulation


  • Apoptosis Regulatory Proteins
  • Calmodulin
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Intracellular Signaling Peptides and Proteins
  • Receptors, Dopamine D2
  • prostate apoptosis response-4 protein
  • Cyclic AMP
  • Calcium
  • Dopamine