Combined loss of M2 and M3 muscarinic acetylcholine receptor (mAChR) function in mutant mice increases serotonin airway responsiveness (AR)
Bibliographic record
Abstract
The lack of mAChR-subtype selective antagonists has made it difficult to define mAChR airway biology. Mutant murine models lacking specific mAChR subtypes are an important experimental tool to define the in vivo role of M2 and M3 mAChRs in AR. Since lack of M3 function results in loss of in vivo ACh AR ( FASEB J 18:711,2004), 5-hydroxytryptamine (5-HT) can be used to assess changes in respiratory system resistance (Rrs) to an i.v. dose-response challenge (5-100 μg/kg). We investigated the impact of combined loss of M2 and M3 function on the 5HT AR phenotype in M2 -/- /M3 -/- double mutant mice. AR to 5HT was assessed in 8 wildtype (WT) and 6 mutant mice that received Alum adjuvant exposure. The Rrs response to 5HT was significantly greater in the M2 -/- /M3 -/- than in the WT mice (max increase 301%+28 vs 102%+ 28.4; p<0.05). In a separate group, we found that the 5HT-AR was predominantly atropine-sensitive in WT (80% inhibition), but methysergide-sensitive in the M2 -/- /M3 -/- mice (100% inhibition). We conclude that loss of M2/M3 function causes an upregulation of 5HT airway responsiveness, which may reflect a change in 5HT receptor expression. Although the molecular mechanisms responsible for the altered phenotype are unclear, our results are an important consideration for the use of mutant mAChR murine models to explore the mechanisms responsible for the development of allergic airway hyperresponsiveness and remodeling. Supported by the Canadian Institutes of Health Research & Ontario Thoracic Society (JF - MOP81211) and the Intramural Research Program of the NIDDKD (JW).
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".