Reductions in the Cardiac Transient Outward K+ Current I-to Caused by Chronic beta-Adrenergic Receptor Stimulation Are Partly Rescued by Inhibition of Nuclear Factor kappa B
Bibliographic record
Abstract
The fast transient outward potassium current (I to,f ) plays a critical role in the electrical and contractile properties of the myocardium.I to,f channels are formed by the co-assembly of the pore-forming ␣-subunits, Kv4.2 and Kv4.3, together with the accessory -subunit KChIP2.Reductions of I to,f are common in the diseased heart, which is also associated with enhanced stimulation of -adrenergic receptors (-ARs).We used cultured neonatal rat ventricular myocytes to examine how chronic -AR stimulation decreases I to,f .To determine which downstream pathways mediate these I to,f changes, adenoviral infections were used to inhibit CaMKII␦c, CaMKII␦b, calcineurin, or nuclear factor B (NF-B).We observed that chronic -AR stimulation with isoproterenol (ISO) for 48 h reduced I to,f along with mRNA expression of all three of its subunits (Kv4.2,Kv4.3, and KChIP2).Inhibiting either CaMKII␦c nor CaMKII␦b did not prevent the ISO-mediated I to,f reductions, even though CaMKII␦c and CaMKII␦b clearly regulated I to,f and the mRNA expression of its subunits.Likewise, calcineurin inhibition did not prevent the I to,f reductions induced by -AR stimulation despite strongly modulating I to,f and subunit mRNA expression.In contrast, NF-B inhibition partly rescued the ISO-mediated I to,f reductions in association with restoration of KChIP2 mRNA expression.Consistent with these observations, KChIP2 promoter activity was reduced by p65 as well as -AR stimulation.In conclusion, NF-B, and not CaMKII␦ or calcineurin, partly mediates the I to,f reductions induced by chronic -AR stimulation.Both mRNA and KChIP2 promoter data suggest that the ISO-induced I to,f reductions are, in part, mediated through reduced KChIP2 transcription caused by NF-B activation.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.008 | 0.003 |
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".