Spliced isoforms of the cardiac Nav1.5 channel modify channel activation by distinct structural mechanisms
Bibliographic record
Abstract
Alternative splicing is an important cellular mechanism that fine tunes the gating properties of both voltage- and ligand-gated ion-channels. The cardiac voltage-gated sodium channel, Nav1.5, is subject to alternative splicing of the DI S3-S4 linker, which generates two types of channels with different activation properties. Here, we show that the gating differences between the adult (mH1) and neonatal (Nav1.5e) isoforms of Nav1.5 are mediated by two amino acid residues: Thr/Ser at position 207 and Asp/Lys at position 211. Electrophysiological experiments, in conjunction with molecular dynamics simulations, revealed that each residue contributes equally to the overall gating shifts in activation, but that the underlying structural mechanisms are different. Asp/Lys at position 211 acts through electrostatic interactions, whereas Thr/Ser at position 207 is predicted to alter the hydrogen bond network at the top of the S3 helix. These distinct structural mechanisms work together to modify movement of the voltage-sensitive S4 helix to bring about channel activation. Interestingly, mutation of the homologous Asp and Thr residues of the skeletal muscle isoform, Nav1.4, to Lys and Ser, respectively, confers a similar gating shift in channel activation, suggesting that these residues may fulfill a conserved role across other Nav channel family members.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".