Differential Protein Kinase C Isoform Regulation and Increased Constitutive Activity of Acetylcholine-Regulated Potassium Channels in Atrial Remodeling
Bibliographic record
Abstract
RATIONALE: Atrial fibrillation (AF) causes atrial-tachycardia remodeling (ATR), with enhanced constitutive acetylcholine-regulated K+ current (I(KAChC)) contributing to action potential duration shortening and AF promotion. The underlying mechanisms are unknown. OBJECTIVE: To evaluate the role of protein-kinase C (PKC) isoforms in ATR-induced I(KAChC) activation. METHODS AND RESULTS: Cells from ATR-dogs (400-bpm atrial pacing for 1 week) were compared to control dog cells. In vitro tachypaced (TP; 3 Hz) canine atrial cardiomyocytes were compared to parallel 1-Hz paced cells. I(KAChC) single-channel activity was assessed in cell-attached and cell-free (inside-out) patches. Protein expression was assessed by immunoblot. In vitro TP activated I(KAChC), mimicking effects of in vivo ATR. Discrepant effects of PKC activation and inhibition between control and ATR cells suggested isoform-selective effects and altered PKC isoform distribution. Conventional PKC isoforms (cPKC; including PKCα) inhibited, whereas novel isoforms (including PKCε) enhanced, acetylcholine-regulated K+ current (I(KACh)) in inside-out patches. TP and ATR downregulated PKCα (by 33% and 37%, respectively) and caused membrane translocation of PKCε, switching PKC predominance to the stimulatory novel isoform. TP increased [Ca2+]i at 2 hours by 30%, with return to baseline at 24 hours. Buffering [Ca2+]i during TP with the cell-permeable Ca2+ chelator BAPTA-AM (1 μmol/L) or inhibiting the Ca2+-dependent protease calpain with PD150606 (20 μmol/L) prevented PKCα downregulation and TP enhancement of I(KAChC). PKCε inhibition with a cell-permeable peptide inhibitor suppressed TP/ATR-induced I(KAChC) activation, whereas cPKC inhibition enhanced I(KAChC) activity in 1-Hz cells. CONCLUSIONS: PKC isoforms differentially modulate I(KACh), with conventional Ca(2+)-dependent isoforms inhibiting and novel isoforms enhancing activity. ATR causes a rate-dependent PKC isoform switch, with Ca2+/calpain-dependent downregulation of inhibitory PKCα and membrane translocation of stimulatory PKCε, enhancing I(KAChC). These findings provide novel insights into mechanisms underlying I(KAChC) dysregulation in AF.
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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 | 0.000 |
| 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".