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.
Beaulieu
Jean-Martin
JM
Department of Cell Biology, Center for Models of Human Disease, Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, North Carolina 27710, USA.
Sotnikova
Tatyana D
TD
Marion
Sébastien
S
Lefkowitz
Robert J
RJ
Gainetdinov
Raul R
RR
Caron
Marc G
MG
D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004298:Dopamine / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D011485:Protein Binding; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*; D015398:Signal Transduction; D009435:Synaptic Transmission; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
C000605254:ARRB2 protein, human; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D015259:Dopamine Agents; C086766:Ppp2r1b protein, mouse; D011518:Proto-Oncogene Proteins; D017448:Receptors, Dopamine D2; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D004298:Dopamine