Role of cardiac ryanodine receptor calmodulin‐binding domains in mediating the action of arrhythmogenic calmodulin N‐domain mutation N54I
Bibliographic record
Abstract
The Ca 2+ ‐sensing protein calmodulin (CaM) inhibits cardiac ryanodine receptor (RyR2)‐mediated Ca 2+ release. CaM mutations associated with arrhythmias and sudden cardiac death have been shown to diminish CaM‐dependent inhibition of RyR2, but the underlying mechanisms are not well understood. Nearly all arrhythmogenic CaM mutations identified are located in the C‐domain of CaM and exert marked effects on Ca 2+ binding to CaM and on the CaM C‐domain interaction with the CaM‐binding domain 2 (CaMBD2) in RyR2. Interestingly, the arrhythmogenic N‐domain mutation CaM‐N54I has little or no effect on Ca 2+ binding to CaM or the CaM C‐domain‐RyR2 CaMBD2 interaction, unlike all CaM C‐domain mutations. This suggests that CaM‐N54I may diminish CaM‐dependent RyR2 inhibition by affecting CaM N‐domain interactions with RyR2 CaMBDs other than CaMBD2. To explore this possibility, we assessed the effects of deleting each of the four known CaMBDs in RyR2 (CaMBD1a, ‐1b, ‐2, or ‐3) on the CaM‐dependent inhibition of RyR2‐mediated Ca 2+ release in HEK293 cells. We found that removing CaMBD1a, CaMBD1b, or CaMBD3 did not alter the effects of CaM‐N54I or CaM‐WT on RyR2 inhibition. On the other hand, deleting RyR2‐CaMBD2 abolished the effects of both CaM‐N54I and CaM‐WT. Our results support that CaM‐N54I causes aberrant RyR2 regulation via an uncharacterized CaMBD or less likely CaMBD2, and that RyR2 CaMBD2 is required for the actions of both N‐ and C‐domain CaM mutations. Moreover, our results show that CaMBD1a is central to RyR2 regulation, but CaMBD1a, CaMBD1b, and CaMBD3 are not required for CaM‐dependent inhibition of RyR2 in HEK293 cells.
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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 | 0.001 | 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 | 0.000 | 0.001 |
| 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".