Caffeine induces Ca2+ release by reducing the threshold for luminal Ca2+ activation of the ryanodine receptor
Bibliographic record
Abstract
Caffeine has long been used as a pharmacological probe for studying RyR (ryanodine receptor)-mediated Ca(2+) release and cardiac arrhythmias. However, the precise mechanism by which caffeine activates RyRs is elusive. In the present study, we investigated the effects of caffeine on spontaneous Ca(2+) release and on the response of single RyR2 (cardiac RyR) channels to luminal or cytosolic Ca(2+). We found that HEK-293 cells (human embryonic kidney cells) expressing RyR2 displayed partial or 'quantal' Ca(2+) release in response to repetitive additions of submaximal concentrations of caffeine. This quantal Ca(2+) release was abolished by ryanodine. Monitoring of endoplasmic reticulum luminal Ca(2+) revealed that caffeine reduced the luminal Ca(2+) threshold at which spontaneous Ca(2+) release occurs. Interestingly, spontaneous Ca(2+) release in the form of Ca(2+) oscillations persisted in the presence of 10 mM caffeine, and was diminished by ryanodine, demonstrating that unlike ryanodine, caffeine, even at high concentrations, does not hold the channel open. At the single-channel level, caffeine markedly reduced the threshold for luminal Ca(2+) activation, but had little effect on the threshold for cytosolic Ca(2+) activation, indicating that the major action of caffeine is to reduce the luminal, but not the cytosolic, Ca(2+) activation threshold. Furthermore, as with caffeine, the clinically relevant, pro-arrhythmic methylxanthines aminophylline and theophylline potentiated luminal Ca(2+) activation of RyR2, and increased the propensity for spontaneous Ca(2+) release, mimicking the effects of disease-linked RyR2 mutations. Collectively, our results demonstrate that caffeine triggers Ca(2+) release by reducing the threshold for luminal Ca(2+) activation of RyR2, and suggest that disease-linked RyR2 mutations and RyR2-interacting pro-arrhythmic agents may share the same arrhythmogenic mechanism.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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 | 0.001 | 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 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".