Proteolytic Digestion Reveals Novel Insights into the Kv1.5 Structure‐Function Relationship
Bibliographic record
Abstract
Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. Kv1.5 channel mediated ultra‐rapidly activating delayed rectifier potassium current (I Kur ) is important for atrial repolarization. Since cardiac I Kur is expressed solely in the atria, therapies that target Kv1.5 represent promising strategies for treating AF. Pathologies linked to AF, such as ischemia and hypoxia, have been reported to activate various proteases. It has been shown that cell‐surface Kv1.5 channels are sensitive to cleavage by extracellular proteases, such as proteinase K (PK). In this study, we investigated the consequences of proteolytic digestion on Kv1.5 channels. Our data demonstrate that extracellularly applied PK cleaves mature (75 kDa) Kv1.5 channels at a single locus in the S1‐S2 linker, yielding two digestion products of 42 and 33 kDa, corresponding to the N‐ and C‐terminal fragments, respectively. Surprisingly, whole‐cell patch clamp analysis showed that I Kv1.5 was unaltered by the PK cut. Plasma membrane protein isolation via biotinylation indicated that both the N‐ and C‐terminal fragments following PK digestion retain cell‐surface expression over several hours. Co‐immunoprecipitation studies after PK cleavage indicate that the two fragments of the channel do not associate. The time‐dependent decline in the Kv1.5 fragment lacking the N‐terminus and the S1 domain paralleled the amplitude of recorded Kv1.5 currents. Our results suggest that Kv1.5 remains functional without the NH 2 ‐S1 portion of the channel. The resistance of I Kv1.5 to proteolytic cleavage may represent an inherent protective mechanism for Kv1.5 function. These findings extend our understanding of the Kv1.5 channel structure‐function relationship. Supported by CIHR & the Heart and Stroke Foundation
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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".