Abstract 9723: Calcium Loading Induces a PKC Isoform Switch That Activates Constitutive Acetylcholine Regulated Potassium Current in Atrial Fibrillation-Related Remodeling
Bibliographic record
Abstract
Background: AF causes atrial tachycardia remodeling (ATR), with enhanced constitutive acetylcholine regulated K + current (I KAChc ) contributing to ATR-induced APD shortening and AF promotion. The present study examined the mechanisms underlying I KAChc activation; based on preliminary evidence for an essential role of phosphorylation, we evaluated the participation of protein kinase C (PKC). Methods: Cultured dog atrial cardiomyocytes in vitro tachypaced (TP) at 3 Hz for 24 hours were compared to parallel 1 Hz paced cells and cells from ATR dogs (paced in vivo at 400 bpm x 1 week). I KAChc single channel activity was assessed in cell attached and cell free (I-O) patches. Protein expression was assessed by Western blot. Results: In vitro TP for 24 hours activated I KAChc (Fig A), mimicking effects of in vivo ATR. The classical PKC isoform PKCα inhibited, whereas the novel isoform PKCε enhanced, I KAChc when applied to the intracellular side of I-O patches. TP and ATR downregulated PKCα (by 33, 37% respectively) and caused membrane translocation of PKCε, switching PKC-predominance to the stimulatory novel isoform. TP increased [Ca 2+ ] i at 2 hours by 30% (Fig B), with subsequent return to baseline at 24 hrs. Ca 2+ activates calpain, which breaks down proteins. Decreasing calpain activity during TP with PD150606 (20 µM) prevented TP enhancement of I KAChc (Fig C). Decreasing [Ca 2+ ] i during TP with BAPTA-AM (1 µM), a cell permeable Ca 2+ chelator, also prevented TP-enhancement of I KAChc (Fig D). Both PD150606 and BAPTA-AM prevented downregulation of PKCα protein expression by TP. Exposure of TP cells to a PKCε inhibitor (Fig E) suppressed TP-induced I KAChc activation, whereas a PKCα inhibitor (Fig F) enhanced I KAChc activity in 1 Hz cells. Conclusions: Rate-related [Ca 2+ ] i loading due to ATR causes a PKC isoform switch, with downregulation of inhibitory PKCα and membrane translocation (activation) of stimulatory PKCε, which enhances I KAChc causing APD shortening and AF promotion.
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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) | 0.000 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".