Interactions between the oxytocin and beta2 adrenergic receptors in human myometrial cells: functional and physical analysis
Why this work is in the frame
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Bibliographic record
Abstract
The human myometrium is endowed with a vast array of receptors that transmit messages encoded in the external stimuli to the interior of the cell. These include the oxytocin receptor (OTR) and the beta2-adrenergic receptor (beta2AR), mediating uterine contractions and relaxation, respectively. These two receptors belong to the superfamily of G protein-coupled receptors (GPCRs) and are important pharmacological targets because OTR antagonists and beta2AR agonists are used to control pre-term uterine contractions. Although they have opposing effects on the myometrium, both receptors activate the MAP kinases ERK1/2, which have been implicated in uterine contractions and the onset of labour. However, the precise mechanisms by which the OTR and the beta2AR activate ERK1/2 in a human myometrial cells remains to be characterized. Further, crosstalk between the beta2AR and OTR signalling has been shown in the myometrium, but it is unclear what mechanisms underlie such crosstalk. In the present study, we describe a novel molecular mechanism for beta2AR-mediated ERK1/2 activation in the human myometrial hTERT-C3 cell line, which involves the activation of a pathway involving Galphai-PI3kinase-PKCzeta and Src. We further show that this signalling cascade is dependent on the presence of the OTR. We also demonstrate physical interactions between OTR and beta2AR using co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and protein-fragment complementation (PCA) assays in HEK 293 cells. In the context of a receptor heterodimer, these interactions allow for allosteric control of one receptor partner by the other, shown here on the example of ERK1/2 activation in the hTERT-C3 cell line. This study illustrates the notion that formation of GPCR heterodimers can generate receptors with unique properties distinct from individual receptors. Understanding how dimerization is arranged and controlled and more importantly the resulting signalling and pharmacology of such complexes will be crucial for future drug design.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| 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 it