Identification and characterization of novel beta-2 adrenegic receptor interacting partners
Bibliographic record
Abstract
Beta2-adrenergic receptors (beta2ARs) are predominantly expressed in cardiomyocytes and regulate cardiac contractility. Prolonged stimulation of these receptors can cause detrimental as well as beneficial effects during heart failure. The ability to transduce these different signals is thought to occur via their association into specific multiprotein complexes containing specific set of heterotrimeric G proteins, effectors, and several other interacting partners that modulate their biosynthesis, signalling, and trafficking. The initial interaction of components comprising these signalling complexes occurs at the level of the endoplasmic reticulum (ER) and at present many of the proteins and processes mediating their assembly remain unknown. In order to identify these proteins and candidate processes, we developed a novel proteomic approach for beta2AR purification. We validated this approach by detecting several known interacting partners of beta2AR in HEK 293 cells including adenylyl cyclase 3, N-ethylmaleimide-sensitive factor, ubiquitin, Na+/H+ exchanger regulatory factor 2 (NHERF2) and of course heterotrimeric G proteins. In addition, we identified and confirmed VCP, gp78 and RNF5, proteins related to ER-associated degradation (ERAD), as novel interacting partners of beta2AR. We demonstrated that VCP retrotranslocates beta2AR from ER to the cytosol and the receptor is degraded by the cytosolic proteasome. Proteasome inhibition or VCP knockdown decreased receptor interaction with Gbetagamma and led to an enhanced signalling response via ERK1/2. We conclude that ERAD specifically regulates levels of uncomplexed beta2ARs to Gbetagamma thus has a previously uncharacterized role in quality control of signalling complex assembly. A better understanding of this process might lead to novel therapeutic strategies during clinical conditions such as heart failure where the nature of receptor signalling complexes changes dramatically.
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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) | 0.000 | 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) | 0.001 | 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".