Abstract 16623: Wnt Signaling Inhibits T-Type Calcium Channels in Cardiomyocytes
Bibliographic record
Abstract
Introduction: The Wnt/β-catenin pathway plays a critical role in embryonic heart development but is mostly inactive in adult hearts. Recent studies have shown that the pathway is re-activated in many heart diseases including myocardial infarction, cardiac hypertrophy and heart failure. Previous work from our laboratory demonstrated that activation of the Wnt/β-catenin pathway reduces the voltage-gated Na + current (I Na ) in neonatal rat ventricular myocytes (NRVMs). In this study, we examined the effects of Wnt signalling on T-type calcium channels (Ca v 3.1), which play a key role in the pacemaker function of the sinoatrial node (SAN). Methods: NRVMs were treated with Wnt3a protein or CHIR-99021, which activates the Wnt/β-catenin pathway by GSK-3β inhibition. PCR array assays, RT-qPCR, and western blot were used to examine changes in mRNA and protein levels of ion channels. To investigate the impact of ion channel alterations on SAN function, a protocol was developed to isolate SAN tissue from mouse hearts and maintain it ex vivo during ECG recording and drug perfusion. Results: PCR array assays showed a 72% reduction in mRNA of Cacna1g (encoding Ca v 3.1) by treatment with Wnt3a protein (130.4±13.2 in control cells vs. 37.4±2.4 in Wnt3a-treated cells, n=4, p<0.05). RT-qPCR and western blot analyses showed a dose-dependent reduction (p<0.05, n=4) in Cacna1g mRNA and Ca v 3.1 protein levels in NRVMs treated with CHIR-99021. Patch-clamp recording also revealed recued T-type calcium current in NRVMs treated with CHIR. Ex vivo perfusion of mouse SANs with a small molecule inhibitor of I Na , flecainide, led to slowed conduction velocity and sinus-exit block in a dose-dependent manner (p<0.05, n=5). Conclusion: The Wnt/β-catenin pathway regulates the expression of both T-type Ca 2+ channels and voltage-gated Na + channels, which are important for impulse generation and conduction in the SAN. Thus, the Wnt pathway may play a role in sinoatrial node dysfunction.
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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) | 0.001 | 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) | 0.007 | 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".