Functional Characterization of CaVα2δ Mutations Associated with Sudden Cardiac Death
Bibliographic record
Abstract
L-type Ca 2+ channels play a critical role in cardiac rhythmicity. These ion channels are oligomeric complexes formed by the pore-forming Ca V α1 with the auxiliary Ca V β and Ca V α2δ subunits. Ca V α2δ increases the peak current density and improves the voltage-dependent activation gating of Ca V 1.2 channels without increasing the surface expression of the Ca V α1 subunit. The functional impact of genetic variants of CACNA2D1 (the gene encoding for Ca V α2δ), associated with shorter repolarization QT intervals (the time interval between the Q and the T waves on the cardiac electrocardiogram), was investigated after recombinant expression of the full complement of L-type Ca V 1.2 subunits in human embryonic kidney 293 cells. By performing side-by-side high resolution flow cytometry assays and whole-cell patch clamp recordings, we revealed that the surface density of the Ca V α2δ wild-type protein correlates with the peak current density. Furthermore, the cell surface density of Ca V α2δ mutants S755T, Q917H, and S956T was not significantly different from the cell surface density of the Ca V α2δ wild-type protein expressed under the same conditions. In contrast, the cell surface expression of Ca V α2δ D550Y, Ca V α2δ S709N, and the double mutant D550Y/Q917H was reduced, respectively, by ≈30–33% for the single mutants and by 60% for the latter. The cell surface density of D550Y/Q917H was more significantly impaired than protein stability, suggesting that surface trafficking of Ca V α2δ was disrupted by the double mutation. Co-expression with D550Y/Q917H significantly decreased Ca V 1.2 currents as compared with results obtained with Ca V α2δ wild type. It is concluded that D550Y/Q917H reduced inward Ca 2+ currents through a defect in the cell surface trafficking of Ca V α2δ. Altogether, our results provide novel insight in the molecular mechanism underlying the modulation of Ca V 1.2 currents by Ca V α2δ. Background: Missense mutations in Ca V α2δ1, an auxiliary subunit of cardiac L-type Ca V 1.2 channels, are associated with arrhythmias. Results: The reduction in the cell surface density of Ca V α2δ1 D550Y/Q917H was sufficient to impair Ca V 1.2 currents. Conclusion: Defects in the cell surface trafficking of Ca V α2δ1 mutants down-regulate L-type currents. Significance: CACNA2D1 genetic variants may trigger arrhythmias by reducing L-type Ca 2+ currents.
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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".