Development and Characterization of Pepducins as Gs-biased Allosteric Agonists*
Bibliographic record
Abstract
The β 2 -adrenergic receptor (β 2 AR) is a prototypical G protein-coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β 2 AR-dependent cAMP production that ultimately promotes airway relaxation. Chronic stimulation of the β 2 AR by long acting β-agonists used in the treatment of asthma can promote attenuated responsiveness to agonists and an increased frequency of fatal asthmatic attacks. β 2 AR desensitization to β-agonists is primarily mediated by G protein-coupled receptor kinases and β-arrestins that attenuate receptor-G s coupling and promote β 2 AR internalization and degradation. A biased agonist that can selectively stimulate G s signaling without promoting receptor interaction with G protein-coupled receptor kinases and β-arrestins should serve as an advantageous asthma therapeutic. To identify such molecules, we screened ∼50 lipidated peptides derived from the intracellular loops of the β 2 AR, known as pepducins. This screen revealed two classes of G s -biased pepducins, receptor-independent and receptor-dependent, as well as several β-arrestin-biased pepducins. The receptor-independent G s -biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependent G s -biased pepducins appear to stabilize a G s -biased conformation of the β 2 AR that couples to G s but does not undergo G protein-coupled receptor kinase-mediated phosphorylation or β-arrestin-mediated internalization. Functional studies in primary human airway smooth muscle cells demonstrate that G s -biased pepducins are not subject to conventional desensitization and thus may be good candidates for the development of next generation asthma therapeutics. Our study reports the first G s -biased activator of the β 2 AR and provides valuable tools for the study of β 2 AR function.A G s -biased agonist for the β 2 -adrenergic receptor (β 2 AR) has yet to be reported. Results A screen of β 2 AR pepducins identified receptor-dependent and receptor-independent pepducins that selectively activate G s . Conclusion Receptor-dependent pepducins promote a G s -biased conformation of the β 2 AR, whereas receptor-independent pepducins directly activate G s . Significance G s -biased pepducins provide a valuable tool for the continued study of β 2 AR function and may prove useful as next-generation asthma therapeutics.
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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 | 0.000 | 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) | 0.000 | 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".