Extracellular ATP increases agonist potency and reduces latency at class B G protein-coupled receptors
Bibliographic record
Abstract
Class B G protein-coupled receptors (GPCRs) are peptide hormone receptors, many of which, such as parathyroid hormone receptor 1, calcitonin receptor (CTR), and corticotropin-releasing factor receptor (CRF1R), are established or emerging therapeutic targets. Previously, we showed that extracellular ATP and related molecules act as positive modulators of parathyroid hormone receptor 1 signaling through an undefined mechanism. Here, we investigated whether ATP enhances signaling by other members of the class B family of GPCRs. Cyclic AMP (cAMP) accumulation was monitored in cells expressing a bioluminescent sensor. Extracellular ATP, which did not induce cAMP accumulation on its own, potentiated agonist-induced cAMP accumulation mediated by CTR, CRF1R, calcitonin receptor-like receptor, pituitary adenylyl cyclase-activating polypeptide receptor 1, and vasoactive intestinal peptide receptors 1 and 2. ATP induced a comparable effect on agonist-stimulated recruitment of β-arrestin to pituitary adenylyl cyclase-activating polypeptide receptor 1. Depending on the receptor and agonist, ATP increased agonist potency by up to 50-fold. The enhancing effect of ATP was mimicked by cytidine 5'-monophosphate, ruling out involvement of purinergic receptors, ATPase activity, or ectokinase activity. For certain receptors (CTR, calcitonin receptor-like receptor + receptor activity-modifying protein 1, and CRF1R), there were temporal lags of up to 30 minutes following agonist application before maximal rates of cAMP accumulation were reached. Lag duration decreased with increasing agonist concentration, suggesting an inverse relationship with receptor occupancy. ATP virtually abolished this temporal lag, even at relatively low agonist concentrations. Thus, ATP both increases the potency of orthosteric agonists at class B GPCRs and reduces latency for adenylyl cyclase activation. SIGNIFICANCE STATEMENT: In addition to acting as a positive modulator of PTH1R signaling, extracellular ATP increases the potency of orthosteric agonists at other class B GPCRs and reduces the latency for adenylyl cyclase activation. Further insight into the precise mechanism of ATP-mediated potentiation of class B GPCR signaling may identify new targets for the development of therapeutic agents aimed at the treatment of endocrine disorders.
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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 | 0.001 |
| 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".