Par-4 links dopamine signaling and depression.

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.
Mesh Terms:
Amino Acid Motifs, Amino Acid Sequence, Animals, Apoptosis Regulatory Proteins, Calcium, Calmodulin, Cells, Cultured, Corpus Striatum, Cyclic AMP, Cyclic AMP Response Element-Binding Protein, Depression, Dopamine, Intracellular Signaling Peptides and Proteins, Mice, Mice, Mutant Strains, Molecular Sequence Data, Mutation, Neurons, Receptors, Dopamine D2, Signal Transduction, Up-Regulation
Cell
Date: Jul. 29, 2005
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