Hetero-oligomerization between β2- and β3-Adrenergic Receptors Generates a β-Adrenergic Signaling Unit with Distinct Functional Properties
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Bibliographic record
Abstract
The ability of the closely related beta(2)- and beta(3)-adrenergic receptors (AR) to form hetero-oligomers was assessed by bioluminescence resonance energy transfer. Quantitative bioluminescence resonance energy transfer titration curves revealed that the beta(2)AR has identical propensity to hetero-oligomerize with the beta(3)AR than to form homo-oligomers. To determine the influence of heterooligomerization, a HEK293 cell line stably expressing an excess of beta(3)AR over beta(2)AR was generated so that all beta(2)AR are engaged in hetero-oligomerization with beta(3)AR, providing a tool to study the effect of hetero-oligomerization on beta(2)AR function in the absence of any beta(2)AR homooligomer. The hetero-oligomerization had no effect on the ligand binding properties of various beta(2)AR ligands and did not affect the potency of isoproterenol to stimulate adenylyl cyclase. Despite the unaltered ligand binding properties of the beta(2/3)AR hetero-oligomer, the stable association of the beta(2)AR with the beta(3)AR completely blocked agonist-stimulated internalization of the beta(2)AR. Given that the beta(3)AR is resistant to agonist-promoted endocytosis, the results indicate that the beta(3)AR acted as a dominant negative of the beta(2)AR endocytosis process. Consistent with this notion, the beta(2/3)AR hetero-oligomer displayed a lower propensity to recruit beta-arrestin-2 than the beta(2)AR. The hetero-oligomerization also led to a change in G protein coupling selectivity. Indeed, in contrast to beta(2)AR and beta(3)AR, which regulate adenylyl cyclase and extracellular signal-regulated kinase activity through a coupling to G(s) and G(i/o), no G(i/o) coupling was observed for the beta(2/3)AR hetero-oligomer. Together, these results demonstrate that hetero-oligomerization between beta(2)AR and beta(3)AR forms a beta-adrenergic signaling unit that possesses unique functional properties.
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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 | 0.000 | 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 it