<i>In silico</i> analysis of the dynamic regulation of cardiac electrophysiology by K<sub>v</sub>11.1 ion‐channel trafficking
Bibliographic record
Abstract
Abstract Cardiac electrophysiology is regulated by continuous trafficking and internalization of ion channels occurring over minutes to hours. Kv11.1 (also known as hERG) underlies the rapidly activating delayed‐rectifier K+ current (IKr), which plays a major role in cardiac ventricular repolarization. Experimental characterization of the distinct temporal effects of genetic and acquired modulators on channel trafficking and gating is challenging. Computer models are instrumental in elucidating these effects, but no currently available model incorporates ion‐channel trafficking. Here, we present a novel computational model that reproduces the experimentally observed production, forward trafficking, internalization, recycling and degradation of Kv11.1 channels, as well as their modulation by temperature, pentamidine, dofetilide and extracellular K+. The acute effects of these modulators on channel gating were also incorporated and integrated with the trafficking model in the O'Hara–Rudy human ventricular cardiomyocyte model. Supraphysiological dofetilide concentrations substantially increased Kv11.1 membrane levels while also producing a significant channel block. However, clinically relevant concentrations did not affect trafficking. Similarly, severe hypokalaemia reduced Kv11.1 membrane levels based on long‐term culture data, but had limited effect based on short‐term data. By contrast, clinically relevant elevations in temperature acutely increased IKr due to faster kinetics, while after 24 h, IKr was decreased due to reduced Kv11.1 membrane levels. The opposite was true for lower temperatures. Taken together, our model reveals a complex temporal regulation of cardiac electrophysiology by temperature, hypokalaemia, and dofetilide through competing effects on channel gating and trafficking, and provides a framework for future studies assessing the role of impaired trafficking in cardiac arrhythmias. image Key points Kv11.1 channels underlying the rapidly activating delayed‐rectifier K+ current are important for ventricular repolarization and are continuously shuttled from the cytoplasm to the plasma membrane and back over minutes to hours. Kv11.1 gating and trafficking are modulated by temperature, drugs and extracellular K+ concentration but experimental characterization of their combined effects is challenging. Computer models may facilitate these analyses, but no currently available model incorporates ion‐channel trafficking. We introduce a new two‐state ion‐channel trafficking model able to reproduce a wide range of experimental data, along with the effects of modulators of Kv11.1 channel functioning and trafficking. The model reveals complex dynamic regulation of ventricular repolarization by temperature, extracellular K+ concentration and dofetilide through opposing acute (millisecond) effects on Kv11.1 gating and long‐term (hours) modulation of Kv11.1 trafficking. This in silico trafficking framework provides a tool to investigate the roles of acute and long‐term processes on arrhythmia promotion and maintenance.
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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 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".