title: Par-4 links dopamine signaling and depression.
abstract: 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.
authors.affiliation: Department of Pathology, Howard Hughes Medical Institute, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
authors.forename: Sang Ki
authors.initials: SK
authors.lastname: Park
authors.forename: Minh Dang
authors.initials: MD
authors.lastname: Nguyen
authors.forename: André
authors.initials: A
authors.lastname: Fischer
authors.forename: Margaret Po-Shan
authors.initials: MP
authors.lastname: Luke
authors.forename: El Bachir
authors.initials: el B
authors.lastname: Affar
authors.forename: Paul Brian
authors.initials: PB
authors.lastname: Dieffenbach
authors.forename: Huang-Chun
authors.initials: HC
authors.lastname: Tseng
authors.forename: Yang
authors.initials: Y
authors.lastname: Shi
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003863:Depression / Q000378:metabolism* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D002147:Calmodulin; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D017448:Receptors, Dopamine D2; C101296:prostate apoptosis response-4 protein; D000242:Cyclic AMP; D002118:Calcium; D004298:Dopamine