The DISC1 R264Q variant increases affinity for the dopamine D2 receptor and increases GSK3 activity

Abstract

AbstractThe Disrupted in schizophrenia 1 (DISC1) gene encodes a scaffolding protein that is involved in many neural functions such as neurogenesis, neural differentiation, embryonic neuron migration and neurotransmitter signalling. DISC1 was originally implicated in schizophrenia in a single family with a drastic mutation, a chromosomal translocation severing the mid-point of the gene (aa 598). Some common DISC1 variants have also been associated with schizophrenia in the general population, but those located far from the chromosomal translocation breakpoint likely have a different functional impact. We previously reported that DISC1 forms a protein complex with dopamine D2 receptor (D2R), the main target for antipsychotic medications. The D2R-DISC1 complex is elevated in brain tissue from schizophrenia patients and facilitates glycogen synthase kinase (GSK)-3 signaling. The DISC1 R264Q variant is located within the region that binds the D2R, and we found that this polymorphism increases the affinity of DISC1 for the D2R and promotes GSK3 activity. Our results suggest a possible mechanism by which this common polymorphism could affect aspects of brain function that are relevant to psychosis and schizophrenia. This provides additional insight into molecular mechanisms underlying schizophrenia that could be exploited in the development of novel pharmacological treatments.