Nuclear Factor κB Downregulates the Transient Outward Potassium Current <i>I</i> <sub>to,f</sub> Through Control of KChIP2 Expression
Bibliographic record
Abstract
RATIONALE: The fast transient outward K(+) current (I(to,f)) plays a critical role in early repolarization of the heart. I(to,f) is consistently downregulated in cardiac disease. Despite its importance, the regulation of I(to,f) in disease remains poorly understood. OBJECTIVE: Because the transcription factor nuclear factor (NF)-κB is activated in cardiac hypertrophy and disease, we studied the role of NF-κB in mediating I(to,f) reductions induced by hypertrophy. METHODS AND RESULTS: Culturing neonatal rat ventricular myocytes in the presence of phenylephrine (PE) plus propranolol (Pro), to selectively activate α(1)-adrenergic receptors, caused reductions in I(to,f), as well as KChIP2 and Kv4.3 expression, while increasing Kv4.2 expression. Inhibition of NF-κB, via overexpression of a phosphorylation-deficient mutant of IκBα (IκBαSA) prevented PE/Pro-induced reductions in I(to,f) and KChIP2 mRNA, without affecting Kv4.2 or Kv4.3 expression, suggesting NF-κB mediates the I(to,f) reductions by repressing KChIP2. Indeed, overexpression of the NF-κB activator IκB kinase-β also decreased KChIP2 expression and I(to,f) (despite increasing Kv4.2), whereas IκBαSA overexpression elevated KChIP2 and decreased Kv4.2 levels. In addition, the classic NF-κB activator tumor necrosis factor α also induced NF-κB-dependent reductions of KChIP2 and I(to,f). Finally, inhibition of calcineurin did not prevent PE/Pro-induced reductions in KChIP2. CONCLUSIONS: NF-κB regulates KChIP2 and Kv4.2 expression. The reductions in I(to,f) observed following α-adrenergic receptor stimulation or tumor necrosis factor α application require NF-κB-dependent decreases in KChIP2 expression.
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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 | 0.000 | 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) | 0.000 | 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".