RYR2 phosphomutants show that the tetramers and the junctional sarcoplasmic reticulum form a structural syncytium.
Bibliographic record
Abstract
We previously showed that RYR2 tetramers are distributed nonuniformly within ventricular dyads, and that physiological and pathological factors can alter their relative positions. Agents that decreased Ca2+ spark frequency, high Mg2+, and saturating concentrations of the immunophilins FKBP12 and FKBP12.6 drew the receptors together, minimizing their nearest-neighbor distance and reducing the size of the clusters. Activating kinases with a phosphorylation cocktail did the opposite. The purpose of this study is to test the hypothesis that phosphorylation of RYR2 is required for the structural changes we have observed. We measured junctional sarcoplasmic reticulum (jSR) lengths using 2-D transmission electron microscopy (TEM) and directly visualized RYR2 distribution using dual-tilt electron tomography in phosphomutant mice S2808A, S2814A, S2814D, and S2030A. Mouse hearts were hung on a Langendorff and treated with either saline or 300 nmol/liter isoproterenol (ISO) for 2 min before being fixed and sectioned for analysis. We found that (1) RYR2 distribution in mouse ventricles is comparable to that reported for rats and humans, (2) the response to ISO applied to an intact, beating heart is identical to a phosphorylation cocktail applied to isolated permeabilized myocytes, and (3) all of the mutations produced significant changes in the tetramer arrangements and/or NND relative to wild-type (WT) mice. Our 2-D TEM measurements showed that (1) in WT mice, ISO significantly increased the length of the jSR, (2) ISO significantly increased the jSR lengths of WT, S2814A, and S2808A mice, but not the S2030A mouse, and (3) the jSR length of the S2814D mouse was significantly greater than WT, but not WT + ISO or S2814D + ISO, indicating that a mutation of the RYR2 alone caused a significant change in the jSR length. These results indicate that the tetramers and the jSR form a structural syncytium.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".