Diminished inhibition and facilitated activation of RyR2‐mediated Ca<sup>2+</sup> release is a common defect of arrhythmogenic calmodulin mutations
Bibliographic record
Abstract
A number of calmodulin (CaM) mutations cause severe cardiac arrhythmias, but their arrhythmogenic mechanisms are unclear. While some of the arrhythmogenic CaM mutations have been shown to impair CaM‐dependent inhibition of intracellular Ca 2+ release through the ryanodine receptor type 2 (RyR2), the impact of a majority of these mutations on RyR2 function is unknown. Here, we investigated the effect of 14 arrhythmogenic CaM mutations on the CaM‐dependent RyR2 inhibition. We found that all the arrhythmogenic CaM mutations tested diminished CaM‐dependent inhibition of RyR2‐mediated Ca 2+ release and increased store‐overload induced Ca 2+ release (SOICR) in HEK293 cells. Moreover, all the arrhythmogenic CaM mutations tested either failed to inhibit or even promoted RyR2‐mediated Ca 2+ release in permeabilized HEK293 cells with elevated cytosolic Ca 2+ , which was markedly different from the inhibitory action of CaM wild‐type. The CaM mutations also altered the Ca 2+ ‐dependency of CaM binding to the RyR2 CaM‐binding domain. These results demonstrate that diminished inhibition, and even facilitated activation, of RyR2–mediated Ca 2+ release is a common defect of arrhythmogenic CaM mutations.
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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) | 0.000 | 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".