Abstract 18375: A Luminal Calcium Sensing Deficient Mutation of the Cardiac Ryanodine Receptor Diminishes Stress-Induced Ventricular Tachycardias in Calsequestrin Null Mice
Bibliographic record
Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease associated with syncope and sudden cardiac death. Naturally occurring mutations in the cardiac ryanodine receptor (RyR2) and calsequestrin (CASQ2) have been linked to CPVT. The sarcoplasmic reticulum (SR) calcium content and the sensitivity of RyR2 to activation by luminal calcium are some of the key factors determining the propensity for Store Overload Induced Calcium Release (SOICR) and SOICR-evoked VTs. We have recently found that the residue E4782 located in the helix bundle crossing (the ion gate) of the RyR2 calcium release channel acts as a SR store calcium sensor responsible for luminal calcium regulation of RyR2 and SOICR. Interestingly, we found that E4782Q mutation completely protected against SOCR-evoked VTs in a CPVT mouse model harboring the disease-causing RyR2 mutation R4496C. In this present study, we determined whether the E4782Q mutation is capable of rescuing the VT phenotype of the CASQ2 null mice, another mouse model of CPVT. We bred E4872Q+/- mice with the CASQ2 null mice to produce CASQ2-/- or CASQ2+/- with or without the heterozygous E4872Q mutation. After the injection of epinephrine (1.6mg/kg) and caffeine (120mg/kg), CASQ2-/- / E4872Q-/- and CASQ2+/- / E4872Q -/- mice showed long lasting VTs during 30-min of ECG recording (83% and 33%, respectively). On the other hand, CASQ2-/- / E4872Q+/- and CASQ2+/- / E4872Q -/- displayed little or no VTs (6.5% and 0.8%, respectively, p < 0.001, when compared with CASQ2-/- / E4872Q -/-, and CASQ2+/- /E4872Q -/-, n=7~9, for each group). Thus, the E4872Q mutation nearly completely rescued the CPVT phenotype in CASQ2 null mice. These observations indicate that targeting the luminal calcium sensor of the RyR2 calcium release channel represents a new and promising therapeutic strategy for treating CPVT and other calcium mediated cardiac arrhythmias.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".