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

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.

journal_name

Cell

journal_title

Cell

authors

Beaulieu JM,Sotnikova TD,Marion S,Lefkowitz RJ,Gainetdinov RR,Caron MG

doi

10.1016/j.cell.2005.05.012

subject

Has Abstract

pub_date

2005-07-29 00:00:00

pages

261-73

issue

2

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(05)00457-5

journal_volume

122

pub_type

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