The KCNN3 rs13376333 risk variant reduces the SK-current density in isogenic stem cell-derived and native human atrial myocytes
Bibliographic record
Abstract
Abstract Background SK channels are emerging as novel pharmaceutical targets for treating atrial fibrillation (AF). Therefore, the single nucleotide polymorphism (SNP) rs13376333, intronic to the calcium-activated SK3 potassium channel gene, might affect the efficiency of drugs targeting this channel. However, the impact of rs13376333 on SK3 current density and electrophysiological function is unknown. Purpose This study aimed to compare the effects of rs13376333 WT and risk SNPs on the apamin-sensitive SK-current in isogenic hiPSC-derived and native human atrial myocytes. Methods SK currents were recorded in atrial myocytes derived from isogenic hiPSC-lines with the WT or risk SNP at rs13376333 with automated patch-clamp technique and in native atrial myocytes using conventional perforated patch-clamp technique to preserve intracellular calcium homeostasis. SK currents were obtained by subtracting the current recorded after exposure to 100 nM apamin from the corresponding current before exposure to apamin. Results The SK current was proportional to the membrane potential above -40 mV in hiPSC-derived myocytes. Comparison of the current-voltage (I-V) relationship revealed that SK currents were significantly smaller in myocytes harboring the rs13376333 risk SNP than in WT (Two-way ANOVA, p=0.0104 , n=45). Increasing the intracellular calcium concentration to 500 nM strongly increased the SK-current (Two-way ANOVA, p=0.0469, p=40) without affecting the shape of the I-V relationship. However, SK currents remained significantly smaller in myocytes with the risk SNP (Two-way ANOVA, p=0.9545, n=30). Recordings in native human atrial myocytes also showed a smaller apamin-sensitive SK-current density in myocytes from patients carrying the rs13376333 risk SNP at membrane potentials expected to affect the action potential peak and plateau phase (0.24±0.08 in risk vs 0.77±0.25 in WT; p<0.05, n=22). Conclusion Myocytes carrying the KCNN3 rs13376333 risk SNP display a reduced SK current compared to the WT variant, suggesting that the risk variant causes loss of SK channel function. Consequently, the efficiency of SK-channel inhibitors to reverse AF could be compromised in patients carrying the rs1337633 risk allele.
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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) | 0.003 | 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".