Function of the first intracellular loop for human D1 and D5 dopaminergic receptors
Bibliographic record
Abstract
The human D1‐class dopamine receptors (hD1R and hD5R) are positively linked to adenylyl cyclase (AC) activation and play critical physiological roles in the brain. To study the function of their first intracellular loop (IL1), we have designed human D1‐ class mutants (hD1‐PD1 and hD5‐PD1) whereby all serines and threonines of IL1 have been replaced by alanines and valines, respectively. Both PD1 mutants exhibited a loss of dopamine affinity but unaltered binding properties for inverse agonists. Furthermore, constitutive activity of PD1 mutants was abolished, implicating that serines and threonines of IL1 are critical for the transition of D1‐class receptors from inactive (R) to active (R*) states in the absence of activating ligands. Dopamine potencies for hD1‐PD1 and hD5‐PD1 were drastically reduced compared to those of parent receptors. Interestingly, despite such warranted uncoupling from the G protein, both PD1 mutants displayed a higher dopamine‐mediated maximal activation of AC in relation to wild‐types. We speculate that this observation is attributed to an impairment in dopamine‐mediated internalization by PD1 mutants. Taken together, our study has demonstrated that IL1 can modulate ligand binding, G protein‐coupling, and possibly receptor trafficking, poising this region as an important structural determinant for D1‐class receptors. This research was funded by NSERC (grant #203694–2010).
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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".