Specific residues of the 5‐HT1A receptor second and third intracellular domain C‐terminal determine Gβγ or Gαi coupling specificity, respectively
Bibliographic record
Abstract
To address their role in 5‐HT1A receptor–G protein coupling, over sixty random point mutant 5‐HT1A receptors in the second intracellular loop C‐terminal domain (Ci2) ( 143 DYVNKRTPRR 152 ) were generated and most retained agonist binding. Mutants were tested for Gβγ signaling to ACII or PLC, and Gαi coupling. Most Ci2 mutations blocked 5‐HT1A signaling to Gβγ, but several also affected Gαi signaling. Ci2 residues K147, R148/151/152 and P150 were essential for coupling, consistent with an obligatory structural role. Polar residues (T149, N146) were required for Gβγ but not Gαi coupling, suggesting a selective interface with Gβγ. The Y144 residue directed specificity for both Gβγ and Gαi pathways and is predicted to form hydrogen bonds with D133/R134 (Ni2 DRY motif) and E340 (Ci3) to stabilize the G‐protein coupling domain. Consistent with a primary role of Ci3 in Gαi coupling, E340 mutants preferentially abrogated Gαi signaling, but one mutant partly blocked Gβγ signaling as well. Thus, the 5‐HT1A receptor Ci2 domain determines Gβγ specificity and stabilizes Gαi‐mediated signaling, while the Ci3 domain primarily directs Gαi coupling and stabilizes Gβγ coupling. Supported by CIHR.
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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 | 0.001 | 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) | 0.000 | 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".