ATP triggers a robust intracellular [Ca <sup>2+</sup> ]‐mediated signalling pathway in human synovial fibroblasts
Bibliographic record
Abstract
New Findings What is the central question of this study? What are the main [Ca 2+ ] i signalling pathways activated by ATP in human synovial fibroblasts? What is the main finding and its importance? In human synovial fibroblasts ATP acts through a linked G‐protein (G q ) and phospholipase C signalling mechanism to produce IP 3 , which then markedly enhances release of Ca 2+ from the endoplasmic reticulum. These results provide new information for the detection of early pathophysiology of arthritis. Abstract In human articular joints, synovial fibroblasts (HSFs) have essential physiological functions that include synthesis and secretion of components of the extracellular matrix and essential articular joint lubricants, as well as release of paracrine substances such as ATP. Although the molecular and cellular processes that lead to a rheumatoid arthritis (RA) phenotype are not fully understood, HSF cells exhibit significant changes during this disease progression. The effects of ATP on HSFs were studied by monitoring changes in intracellular Ca 2+ ([Ca 2+ ] i ), and measuring electrophysiological properties. ATP application to HSF cell populations that had been enzymatically released from 2‐D cell culture revealed that ATP (10–100 μ m ), or its analogues UTP or ADP, consistently produced a large transient increase in [Ca 2+ ] i . These changes (i) were initiated by activation of the P 2 Y purinergic receptor family, (ii) required G q ‐mediated signal transduction, (iii) did not involve a transmembrane Ca 2+ influx, but instead (iv) arose almost entirely from activation of endoplasmic reticulum (ER)‐localized inositol 1,4,5‐trisphosphate (IP 3 ) receptors that triggered Ca 2+ release from the ER. Corresponding single cell electrophysiological studies revealed that these ATP effects (i) were insensitive to [Ca 2+ ] o removal, (ii) involved an IP 3 ‐mediated intracellular Ca 2+ release process, and (iii) strongly turned on Ca 2+ ‐activated K + current(s) that significantly hyperpolarized these cells. Application of histamine produced very similar effects in these HSF cells. Since ATP is a known paracrine agonist and histamine is released early in the inflammatory response, these findings may contribute to identification of early steps/defects in the initiation and progression of RA.
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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) | 0.001 | 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".