Enhanced Ca <sup>2+</sup> entry due to Orai1 plasma membrane insertion increases IL‐8 secretion by cystic fibrosis airways
Bibliographic record
Abstract
ABSTRACT Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR). The most common mutation, ΔF508, causes retention of CFTR in the endoplasmic reticulum (ER). Some CF abnormalities can be explained by altered Ca 2+ homeostasis, although it remains unknown how CFTR influences calcium signaling. This study examined the novel hypothesis that store‐operated calcium entry (SOCE) through Orai1 is abnormal in CF. The significance of Orai1‐mediated SOCE for increased interleukin‐8 (IL‐8) expression in CF was also investigated. CF and non‐CF human airway epithelial cell line and primary cells (obtained at lung transplantation) were used in Ca 2+ imaging, electrophysiology, and fluorescence imaging experiments to explore differences in Orai1 function in CF vs . non‐CF cells. Protein expression and localization was assessed by Western blots, cell surface biotinylation, ELISA, and image correlation spectroscopy (ICS). We show here that store‐operated Ca 2+ entry (SOCE) is elevated in CF human airway epithelial cells (hAECs; ~1.8‐ and ~2.5‐fold for total Ca 2+ i increase and Ca 2+ influx rate, respectively, and ~2‐fold increase in the I CRAC current) and is caused by increased exocytotic insertion (~2‐fold) of Orai1 channels into the plasma membrane, which is normalized by rescue of ΔF508‐CFTR trafficking to the cell surface. Augmented SOCE in CF cells is a major factor leading to increased IL‐8 secretion (~2‐fold). CFTR normally down‐regulates the Orai1/stromal interaction molecule 1 (STIM1) complex, and loss of this inhibition due to the absence of CFTR at the plasma membrane helps to explain the potentiated inflammatory response in CF cells.—Balghi, H., Robert, R., Rappaz, B., Zhang, X., Wohlhuter‐Haddad, A., Evagelidis, A., Luo, Y., Goepp, J., Ferraro, P., Roméo, P., Trebak, M., Wiseman, P. W., Thomas, D. Y., Hanrahan, J. W. Enhanced Ca 2+ entry due to Orai1 plasma membrane insertion increases IL‐8 secretion by cystic fibrosis airways. FASEB J. 25, 4274–4291 (2011). www.fasebj.org
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".