Abstract 13235: Enhanced Receptor-independent Nucleoside Diphosphate Kinase Mediated G <sub>s</sub> Protein Signaling Contributes to Arrhythmogenic Calcium Mishandling in Atrial Fibrillation
Bibliographic record
Abstract
Background: Enhanced G-protein related cyclic AMP (cAMP) signaling and abnormal Ca 2+ handling due to dysfunctional ryanodine receptor type-2 (RyR2) are implicated in atrial fibrillation (AF). Nucleoside diphosphate kinase (NDPK) forms complexes with G s proteins, increasing cAMP signaling via receptor-independent G protein activation. Here, we studied the possible proarrhythmic role of NDPKs in clinical (chronic AF, cAF) and experimental AF. Methods: NDPK and G protein expression were assessed by immunoblotting in atria from sinus rhythm (Ctl) and cAF patients; dogs undergoing AF-mimicking tachycardia remodeling (ATR, 400 bpm, 7 days) or AF-promoting chronic atrial ischemia; and canine atrial cardiomyocytes (CMs) paced in vitro for 24-48 hrs at 1 (P1) or 3 Hz (P3). cAMP was measured by immunoassay. Immunostaining was used for protein visualization. Spontaneous sarcoplasmic reticulum (SR) Ca 2+ release events (SCaEs) in CMs overexpressing NDPKs or EGFP-control (adenoviral gene-transfer) were recorded with epifluorescence (Indo-1). Results: NDPK-B, NDPK-C, Gα s and Gβ 1 were upregulated in cAF patient atria (Fig A). ATR and chronic atrial ischemia increased NDPK-B expression in canine atria (Fig B). In vitro tachypacing reproduced AF effects on NDPK/Gα s in CMs (Fig C). Accordingly, cAMP levels were higher in cAF patients and P3-paced CMs (Fig D-E). Adenoviral NDPK-B and NDPK-C overexpression increased cAMP levels (Fig F). NDPK-B, NDPK-C and Gα s co-localized at the plasma membrane when upregulated by tachypacing canine CMs. SCaEs, a proarrhythmic consequence of diastolic SR Ca 2+ leak, were enhanced in NDPK-B or NDPK-C overexpressing CMs, and the latency from last regular SR Ca 2+ release was reduced (Fig G). Conclusions: Receptor-independent NDPK-mediated G s -protein/cAMP signaling is upregulated in clinical and experimental AF, causes arrhythmogenic SCaEs, and is likely a novel contributor to ectopy-inducing atrial triggered activity due to SR Ca 2+ leak.
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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) | 0.000 | 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".