Opposite Regulation of Human D1‐like Dopaminergic Responsiveness by Protein Kinase C is Shaped by Two Critical Serine Residues of the Third Intracellular Loop of Human D5 Dopaminergic Receptor
Bibliographic record
Abstract
Phorbol‐12‐myristate‐13‐acetate (PMA), an activator of serine/threonine protein kinase C, promotes in a strikingly opposite fashion sensitization and desensitization of the highly homologous human dopamine D1 and D5 receptors (D1R, D5R), respectively. We identified the third intracellular loop (IL3) as the main structural determinant controlling the opposite PMA‐mediated regulation of D1R and D5R responsiveness using a chimeric approach. Single‐point mutations were made to delineate the residues of D5R‐IL3 region implicated in PMA‐induced D5R desensitization. Dopamine responsiveness of cells transfected with wild‐type or mutant forms of D5R following PMA treatment was assessed using whole cell cAMP assays. Our results show that serine residues 261 and 271 of D5R‐IL3 (corresponding to alanine 230 and asparagine 240 in D1R‐IL3) impart PMA‐induced desensitization to D5R. In fact, D5R mutants harboring single serine‐to‐alanine substitution of residue 261 or 271 display a sensitized responsiveness following PKC activation that was reminiscent of D1R sensitization observed in PMA‐treated cells. Overall, our work suggests that the presence or absence of serine residues located at positions 261 and 271 of D5R‐IL3 or positions 230 and 240 of D1R‐IL3 control the fate of PMA‐mediated regulation of D1‐like responsiveness. Supported by CIHR grant (MOP‐81341 to MT) and FRSQ Graduate Scholarship (to BP).
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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".