A dopamine D2 receptor-DISC1 protein complex may contribute to antipsychotic-like effects

Neuron. 2014 Dec 17;84(6):1302-16. doi: 10.1016/j.neuron.2014.11.007. Epub 2014 Nov 26.


Current antipsychotic drugs primarily target dopamine D2 receptors (D2Rs), in conjunction with other receptors such as those for serotonin. However, these drugs have serious side effects such as extrapyramidal symptoms (EPS) and diabetes. Identifying a specific D2R signaling pathway that could be targeted for antipsychotic effects, without inducing EPS, would be a significant improvement in the treatment of schizophrenia. We report here that the D2R forms a protein complex with Disrupted in Schizophrenia 1 (DISC1) that facilitates D2R-mediated glycogen synthase kinase (GSK)-3 signaling and inhibits agonist-induced D2R internalization. D2R-DISC1 complex levels are increased in conjunction with decreased GSK-3α/β (Ser21/9) phosphorylation in both postmortem brain tissue from schizophrenia patients and in Disc1-L100P mutant mice, an animal model with behavioral abnormalities related to schizophrenia. Administration of an interfering peptide that disrupts the D2R-DISC1 complex successfully reverses behaviors relevant to schizophrenia but does not induce catalepsy, a strong predictor of EPS in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amphetamine / pharmacology
  • Animals
  • Antipsychotic Agents / pharmacology*
  • Arrestins / metabolism
  • Brain / metabolism
  • Catalepsy / chemically induced
  • Clathrin / metabolism
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Male
  • Mice
  • Motor Activity / drug effects
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Peptides / pharmacology
  • Phosphorylation
  • Prepulse Inhibition / drug effects
  • Protein Binding / drug effects
  • Rats
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism*
  • Schizophrenia / metabolism*
  • beta-Arrestins


  • Antipsychotic Agents
  • Arrestins
  • Clathrin
  • DISC1 protein, human
  • Disc1 protein, mouse
  • Nerve Tissue Proteins
  • Peptides
  • Receptors, Dopamine D2
  • beta-Arrestins
  • Amphetamine
  • Glycogen Synthase Kinase 3