Role of Cys3602 in the function and regulation of the cardiac ryanodine receptor
Bibliographic record
Abstract
The cardiac Ca²⁺ release channel [ryanodine receptor type 2 (RyR2)] is modulated by thiol reactive agents, but the molecular basis of RyR2 modulation by thiol reagents is poorly understood. Cys³⁶³⁵ in the skeletal muscle RyR1 is one of the most hyper-reactive thiols and is important for the redox and calmodulin (CaM) regulation of the RyR1 channel. However, little is known about the role of the corresponding cysteine residue in RyR2 (Cys³⁶⁰²) in the function and regulation of the RyR2 channel. In the present study, we assessed the impact of mutating Cys³⁶⁰² (C³⁶⁰²A) on store overload-induced Ca²⁺ release (SOICR) and the regulation of RyR2 by thiol reagents and CaM. We found that the C³⁶⁰²A mutation suppressed SOICR by raising the activation threshold and delayed the termination of Ca²⁺ release by reducing the termination threshold. As a result, C³⁶⁰²A markedly increased the fractional Ca²⁺ release. Furthermore, the C³⁶⁰²A mutation diminished the inhibitory effect of N-ethylmaleimide on Ca²⁺ release, but it had no effect on the stimulatory action of 4,4'-dithiodipyridine (DTDP) on Ca²⁺ release. In addition, Cys³⁶⁰² mutations (C³⁶⁰²A or C³⁶⁰²R) did not abolish the effect of CaM on Ca²⁺-release termination. Therefore, RyR2-Cys³⁶⁰² is a major site mediating the action of thiol alkylating agent N-ethylmaleimide, but not the action of the oxidant DTDP. Our data also indicate that residue Cys³⁶⁰² plays an important role in the activation and termination of Ca²⁺ release, but it is not essential for CaM regulation of RyR2.
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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".