Intracellular sorting studies of wild‐type and truncated forms of the D1 dopaminergic receptor unravel a chaperone‐like effect of antipsychotic drugs
Bibliographic record
Abstract
The D1 dopaminergic receptor (D1R) is a seven‐transmembrane protein linked to stimulatory heterotrimeric GTP‐binding proteins. Here, we investigate the role of the cytoplasmic tail (CT) of D1R in regulating intracellular sorting properties of the receptor. We show that wild‐type (WT) D1R and its truncated and phosphorylation‐deficient form (Δ351) were sorted at the plasma membrane of transfected embryonic kidney 293 (HEK293) cells. Antibody feeding and co‐localization studies indicate that similar to WT, Δ351 internalizes through a clathrin‐, CT‐ and receptor phosphorylation‐independent pathway following dopamine (DA) exposure. However, in the absence of DA, Δ351 displays a strong intracellular staining unlike WT as assessed using immunofluorescence studies. Our confocal microscopy analysis shows that Δ351 co‐localizes with the endoplasmic reticulum (ER) markers, calnexin and calreticulin. Intriguingly, we observe an increase in the mature form of Δ351 and a complete rescue of ER‐retained Δ351 following an overnight treatment of transfected HEK293 cells with the inverse agonist flupentixol (Flu), an antipsychotic drug. These data strongly suggest that Flu displays a chaperone‐like effect on ER‐retained Δ351. Overall, our studies underpin a pivotal role of the CT of D1R in regulating the ontogeny and sorting to cell surface of this dopaminergic receptor subtype. Supported by CIHR (MOP‐81341; MT).
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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 | 0.000 | 0.000 |
| 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) | 0.001 | 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 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".