The DISC1 R264Q variant increases affinity for the dopamine D2 receptor and increases GSK3 activity
Bibliographic record
Abstract
The 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.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".