Key result
KCNN3 rs13376333 risk SNP reduces apamin-sensitive SK current density ~69% in human atrial myocytes.
Why the study?
SK channels are emerging pharmaceutical targets for treating AF, but the impact of the KCNN3 intronic SNP rs13376333 on SK3 current density and electrophysiological function is unknown.
Does the KCNN3 rs13376333 risk variant reduce SK-current density in human atrial myocytes compared to the WT variant?
Does the KCNN3 rs13376333 risk variant reduce SK-current density in human atrial myocytes compared to the WT variant?
The KCNN3 rs13376333 risk variant reduces SK current density in human atrial myocytes, suggesting potential reduced efficacy of SK-channel inhibitors for atrial fibrillation in carriers.
May indicate reduced SK-inhibitor efficacy in rs13376333 carriers; hypothesis-generating for genotype-stratified AF trials.
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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Sabado et al. (2025) studied Atrial fibrillation. KCNN3 rs13376333 risk SNP vs. Wild-type (WT) variant was evaluated on Apamin-sensitive SK-current density at membrane potentials affecting action potential peak and plateau phase (p=<0.05). The KCNN3 rs13376333 risk SNP significantly reduced apamin-sensitive SK-current density in native human atrial myocytes compared to the wild-type variant (0.24 vs 0.77; p<0.05).
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