Abstract Fri084: Electrophysiological characterization of L1521I-Ca <sub>v</sub> 1.2 mutation reported in a cardiology patient provides insight into channel structure
Bibliographic record
Abstract
Introduction: Voltage-gated calcium channels (Ca v 1.2, CACNA1C ) activate during the plateau phase of the cardiac action potential (AP). Negative feedback mechanisms that control the channel inactivation are located in the cytosolic C-terminus of Ca v 1.2. Despite efforts, the structure of the C-terminus of Ca v 1.2 has not yet been fully resolved. Hypothesis: We characterised a variant of uncertain significance located within the EF-hand domain and hypothesized that L1521I-Ca v 1.2, reported in a cardiology patient, altered calcium-dependent inactivation (CDI). Aims: To clarify biophysical properties of L1521I-Ca v 1.2 given its location within the EF-hand domain. Methods: The patch-clamp technique was used to record currents and biophysical properties of wt-Ca v 1.2 and L1521I-Ca v 1.2 channels expressed in doxycycline-inducible Flp-In HEK293 cells. Prediction of the functional effects of L1521I-Ca v 1.2 was performed using the PolyPhen-2 bioinformatic tool. Models of the mutant EF-hand domain were prepared using COOT and geometry optimization. Results: Amplitude of the L1521I-Ca v 1.2 channel current did not differ from wt-Ca v 1.2. However, slope (L1521I: 9.9±0.3 mV n=38 vs wt: 8.1±0.33 mV n=53, p<0.001) and V 1/2 (L1521I: 13.2±1.6 mV n=38 vs wt: 5.3±1.6 mV n=53, p<0.001) of the channel fractional activation were altered. V 1/2 of steady-state activation was right-shifted in L1521I-Ca v 1.2 channels (15.3±2.0 mV n=11, vs wt: 8.6±1.7 mV n=19, p<0.05), and window current increased (4.5±0.6 a.u. n=11 vs wt: 2.7±0.3 a.u., n=19 p<0.05). L1521I-Ca v 1.2 delayed CDI and this difference was statistically significant 225 ms after channel activation. Conclusions: Our electrophysiological data suggest that L1521I-Ca v 1.2 is a gain-of-function mutation. L1521I delayed CDI of Ca v 1.2, right-shifted V 1/2 of steady-state activation and augmented window current. L1521 is part of a hydrophobic core and is completely buried. Although in our COOT and geometry optimization model, L1521I mutation is predicted to cause only small perturbations in the Ca v 1.2 structure, we speculate that allosterically it may be sufficient to affect interaction between EF-hand and III-IV linker. Consistent with our in silico modelling, these alterations may be sufficient to prolong the AP and QT interval on ECG.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.002 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".