Wnt signalling suppresses voltage‐dependent Na<sup>+</sup> channel expression in postnatal rat cardiomyocytes
Bibliographic record
Abstract
Key points Wnt signalling is activated in arrhythmogenic heart diseases, but its role in the regulation of cardiac ion channel expression is unknown. Exposure of neonatal rat ventricular myocytes to Wnt3a, an activator of canonical Wnt signalling, decreases Scn5a mRNA, Nav1.5 protein and Na+ current density. Wnt3a does not affect the inward rectifier K+ current or L‐type Ca2+ channels. The Wnt pathway is a negative regulator of cardiac Na+ channel expression and may play a role in altered ion channel expression in heart disease. Abstract Wnt signalling plays crucial roles in heart development, but is normally suppressed postnatally. In arrhythmogenic conditions, such as cardiac hypertrophy and heart failure, Wnt signalling is reactivated. To explore the potential role of Wnt signalling in arrhythmogenic electrical remodelling, we examined voltage‐dependent ion channels in cardiomyocytes. Treatment of neonatal rat ventricular myocytes with either recombinant Wnt3a protein or CHIR‐99021 (CHIR, a glycogen synthase kinase‐3β inhibitor) caused a dose‐dependent increase in Wnt target gene expression (Axin2 and Lef1), indicating activation of the Wnt/β‐catenin pathway. Cardiac Na+ current (INa) density was reduced by Wnt3a (−20 ± 4 vs. control −59 ± 7 pA pF−1, at −30 mV) or CHIR (−22 ± 5 pA pF−1), without changes in steady‐state activation, inactivation or repriming kinetics. Wnt3a and CHIR also produced dose‐dependent reductions in the mRNA level of Scn5a (the cardiac Na+ channel α subunit gene), as well as a 56% reduction (by Wnt3a) in the Nav1.5 protein level. Consistent with INa reduction, action potentials in Wnt3a‐treated neonatal rat ventricular myocytes had a lower upstroke amplitude (91 ± 3 vs. control 137 ± 2 mV) and decreased maximum upstroke velocity (70 ± 10 vs. control 163 ± 15 V s−1). In contrast, inward rectifier K+ current and L‐type Ca2+ channels were not affected by Wnt3a treatment. Taken together, our data indicate that the Wnt/β‐catenin pathway suppresses INa in postnatal cardiomyocytes and may contribute to ion channel remodelling in heart disease.
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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) | 0.002 | 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 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".