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

Cell. 2005 Jul 29;122(2):261-73. doi: 10.1016/j.cell.2005.05.012.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Arrestins / genetics
  • Arrestins / physiology*
  • Corpus Striatum / metabolism
  • Corpus Striatum / physiology
  • Cyclic AMP / metabolism
  • Dopamine / physiology
  • Dopamine Agents / pharmacology
  • Enzyme Activation
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / drug effects
  • Motor Activity / physiology*
  • Phosphoprotein Phosphatases / metabolism*
  • Protein Binding
  • Protein Phosphatase 2
  • Protein-Serine-Threonine Kinases / physiology*
  • Proto-Oncogene Proteins / physiology*
  • Proto-Oncogene Proteins c-akt
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / physiology*
  • Signal Transduction
  • Synaptic Transmission*
  • beta-Arrestin 2
  • beta-Arrestins

Substances

  • ARRB2 protein, human
  • Arrb2 protein, mouse
  • Arrestins
  • Dopamine Agents
  • Ppp2r1b protein, mouse
  • Proto-Oncogene Proteins
  • Receptors, Dopamine D2
  • beta-Arrestin 2
  • beta-Arrestins
  • Cyclic AMP
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2
  • Dopamine