Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Arrestins / genetics
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Arrestins / physiology*
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Corpus Striatum / metabolism
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Corpus Striatum / physiology
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Cyclic AMP / metabolism
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Dopamine / physiology
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Dopamine Agents / pharmacology
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Enzyme Activation
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Motor Activity / drug effects
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Motor Activity / physiology*
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Phosphoprotein Phosphatases / metabolism*
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Protein Binding
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Protein Phosphatase 2
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Protein Serine-Threonine Kinases / physiology*
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Receptors, Dopamine D2 / agonists
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Receptors, Dopamine D2 / physiology*
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Signal Transduction
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Synaptic Transmission*
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beta-Arrestin 2
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beta-Arrestins
Substances
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ARRB2 protein, human
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Arrb2 protein, mouse
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Arrestins
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Dopamine Agents
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Ppp2r1b protein, mouse
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Proto-Oncogene Proteins
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Receptors, Dopamine D2
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beta-Arrestin 2
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beta-Arrestins
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Cyclic AMP
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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Phosphoprotein Phosphatases
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Protein Phosphatase 2
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Dopamine