Ca <sup>2+</sup> -CaM Dependent Inactivation of RyR2 Underlies Ca <sup>2+</sup> Alternans in Intact Heart
Bibliographic record
Abstract
Rationale: Ca 2+ alternans plays an essential role in cardiac alternans that can lead to ventricular fibrillation, but the mechanism underlying Ca 2+ alternans remains undefined. Increasing evidence suggests that Ca 2+ alternans results from alternations in the inactivation of cardiac RyR2 (ryanodine receptor 2). However, what inactivates RyR2 and how RyR2 inactivation leads to Ca 2+ alternans are unknown. Objective: To determine the role of CaM (calmodulin) on Ca 2+ alternans in intact working mouse hearts. Methods and Results: We used an in vivo local gene delivery approach to alter CaM function by directly injecting adenoviruses expressing CaM-wild type, a loss-of-function CaM mutation, CaM (1–4), and a gain-of-function mutation, CaM-M37Q, into the anterior wall of the left ventricle of RyR2 wild type or mutant mouse hearts. We monitored Ca 2+ transients in ventricular myocytes near the adenovirus-injection sites in Langendorff-perfused intact working hearts using confocal Ca 2+ imaging. We found that CaM-wild type and CaM-M37Q promoted Ca 2+ alternans and prolonged Ca 2+ transient recovery in intact RyR2 wild type and mutant hearts, whereas CaM (1–4) exerted opposite effects. Altered CaM function also affected the recovery from inactivation of the L-type Ca 2+ current but had no significant impact on sarcoplasmic reticulum Ca 2+ content. Furthermore, we developed a novel numerical myocyte model of Ca 2+ alternans that incorporates Ca 2+ -CaM-dependent regulation of RyR2 and the L-type Ca 2+ channel. Remarkably, the new model recapitulates the impact on Ca 2+ alternans of altered CaM and RyR2 functions under 9 different experimental conditions. Our simulations reveal that diastolic cytosolic Ca 2+ elevation as a result of rapid pacing triggers Ca 2+ -CaM dependent inactivation of RyR2. The resultant RyR2 inactivation diminishes sarcoplasmic reticulum Ca 2+ release, which, in turn, reduces diastolic cytosolic Ca 2+ , leading to alternations in diastolic cytosolic Ca 2+ , RyR2 inactivation, and sarcoplasmic reticulum Ca 2+ release (ie, Ca 2+ alternans). Conclusions: Our results demonstrate that inactivation of RyR2 by Ca 2+ -CaM is a major determinant of Ca 2+ alternans, making Ca 2+ -CaM dependent regulation of RyR2 an important therapeutic target for cardiac alternans.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| 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".