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 distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".