Dopamine is a neurotransmitter that acts in neuronal circuits that convey reward and motivation. Abnormalities in dopamine signaling are associated with mental illness. In particular, the reduced function of D2-type dopamine receptor (D2DR) is thought to contribute to schizophrenia, drug addiction, and mood disorders. A number of signaling mechanisms have been described, but two new papers identify new components that may represent targets for new therapeutics. Park et al. used a yeast two-hybrid screen to discover Par-4 (prostate apoptosis response 4, a protein previously implicated in promoting apoptosis though interactions with other signaling proteins) as a binding partner for D2DR. Interaction was confirmed by coimmunoprecipitation of the proteins from mouse brain and their localization together in neurons detected by immunohistochemistry. The authors prepared mice that expressed a deletion mutant of Par-4 lacking the domain shown to mediate interaction with D2DR. In cultures of primary striatal neurons from these mice, activation of signaling through cAMP (adenosine 3′,5′-monophosphate) was disrupted. Furthermore, the behavioral tests of the mutant mice showed depression-like behavior but no effects on measures of anxiety. Beaulieu et al. examined another new signaling mechanism for the D2DR. They find that β-arrestin 2 is also important for behavioral effects of dopamine. β-arrestin 2 was shown to associate with protein phosphatase 2a (PP2A) and the protein kinase Akt. This interaction was increased after treatment of animals with dopamine, and in animals lacking β-arrestin 2, PP2A and Akt were not associated. Dopamine causes decreased activity of Akt but failed to do so in animals lacking β-arrestin 2. Such animals also showed decreases in dopamine-dependent behaviors. The arrestin-dependent signals appear to be independent of cAMP signaling, which was not altered in the mice lacking β-arrestin 2. D2DRs are well-established targets of antipsychotic drugs, so both studies provide hope that new understanding of the complexities of dopamine signaling may allow development of more specific therapeutics that could be more effective and have fewer side effects.
J.-M. Beaulieu, T. D. Sotnikova, S. Marion, R. J. Lefkowitz, R. R. Gainetdinov, M. G. Caron, An Akt/β-Arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122, 261-273 (2005). [PubMed]
S. K. Park, M. D. Nguyen, A. Fischer, M. P.-S. Luke, E. B. Affar, P. B. Dieffenbach, H.-C. Tseng, Y. Shi, L.-H. Tsai, Par-4 links dopamine signaling and depression. Cell 122, 275-287 (2005). [PubMed]