Signaling Behavior of Dopamine

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Science  12 Aug 2005:
Vol. 309, Issue 5737, pp. 991
DOI: 10.1126/science.309.5737.991c

Dopamine is a neurotransmitter in circuits that convey reward and motivation, and abnormalities in dopamine signaling have been associated with mental illness. In particular, reduced function of the D2-type dopamine receptor (D2DR) is thought to contribute to schizophrenia, addiction, and mood disorders. Park et al. used a yeast two-hybrid screen to uncover prostate apoptosis response 4 (Par-4) as a binding partner for D2DR. In striatal neurons from mice that expressed a mutant form of Par-4 (in which the domain mediating the interaction with D2DR had been deleted), activation of signaling through cAMP was disrupted. Furthermore, behavioral tests of the mutant mice showed a depression-like phenotype, but no effects on measures of anxiety. Beaulieu et al. examined another signaling pathway emanating from D2DR, and they find that β-arrestin 2 is important in mediating the behavioral effects of dopamine. In wild-type mice, β-arrestin 2 was shown to associate with protein phosphatase 2a (PP2A) and the protein kinase Akt; this interaction increased after treatment with dopamine, which produced a decrease in Akt activity. In contrast, in mice deficient in β-arrestin 2, PP2A and Akt did not associate with D2DR, and dopamine did not affect Akt activity; this latter set of mice also showed decreases in dopamine-dependent behaviors. D2DRs are targets of antipsychotic drugs, so both studies provide hope that understanding the complexities of dopamine signaling may lead to the development of therapeutics that would be more effective and have fewer side effects. - NRG

Cell 122, 275; 261 (2005).

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