Folding Efficiency Is Rate-limiting in Dopamine D4 Receptor Biogenesis
Bibliographic record
Abstract
Dopamine receptors are G protein-coupled receptors that are critically involved in locomotion, reward, and cognitive processes. The D2 class of dopamine receptors (DRD2, -3, and -4) is the target for antipsychotic medication. DRD4 has been implicated in cognition, and genetic studies have found an association between a highly polymorphic repeat sequence in the human DRD4 coding region and attention deficit hyperactivity disorder. Using DRD4 as a model, we show that antipsychotics can function as potent pharmacological chaperones up-regulating receptor expression and can also rescue a non-functional DRD4 folding mutant. This chaperone-mediated up-regulation involves reduced degradation by the 26 S proteasome; likely via the stabilization of newly synthesized receptor in the endoplasmic reticulum. Dopamine itself can function as a chaperone when shuttled into the cell by means of the dopamine transporter. Furthermore, different repeat variants of DRD4 display differential sensitivity to this chaperone effect. These data suggest that folding efficiency may be rate-limiting for dopamine receptor biogenesis and that this efficiency differs between receptor variants. Consequently, the clinical profile of dopaminergic ligands, including antipsychotics, may include their ability to serve as pharmacological chaperones.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.003 |
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 source (direct Gemma or distilled Codex), 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".