An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior.

Dopamine plays an important role in the etiology of schizophrenia, and D2 class dopamine receptors are the best-established target of antipsychotic drugs. Here we show that D2 class-receptor-mediated Akt regulation involves the formation of signaling complexes containing beta-arrestin 2, PP2A, and Akt. beta-arrestin 2 deficiency in mice results in reduction ...
of dopamine-dependent behaviors, loss of Akt regulation by dopamine in the striatum, and disruption of the dopamine-dependent interaction of Akt with its negative regulator, protein phosphatase 2A. Importantly, canonical cAMP-mediated dopamine-receptor signaling is not inhibited in the absence of beta-arrestin 2. These results demonstrate that, apart from its classical function in receptor desensitization, beta-arrestin 2 also acts as a signaling intermediate through a kinase/phosphatase scaffold. Furthermore, this function of beta-arrestin 2 is important for the expression of dopamine-associated behaviors, thus implicating beta-arrestin 2 as a positive mediator of dopaminergic synaptic transmission and a potential pharmacological target for dopamine-related psychiatric disorders.
Mesh Terms:
Animals, Arrestins, Corpus Striatum, Cyclic AMP, Dopamine, Dopamine Agents, Enzyme Activation, Extracellular Signal-Regulated MAP Kinases, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Phosphoprotein Phosphatases, Protein Binding, Protein Phosphatase 2, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-akt, Receptors, Dopamine D2, Signal Transduction, Synaptic Transmission
Cell
Date: Jul. 29, 2005
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