Small conductance calcium-activated potassium current and the mechanism of atrial arrhythmia in mice with dysfunctional melanocyte-like cells

Background The melanin synthesis enzyme dopachrome tautomerase (Dct) regulates intracellular Ca²⁺ in melanocytes. Homozygous Dct knockout (Dct^-/-) adult mice are vulnerable to atrial arrhythmias (AA). Objective The purpose of this study was to determine whether apamin-sensitive small conductance Ca²⁺-activated K⁺ (SK) currents are upregulated in Dct^-/- mice and contribute to AA. Methods Optical mapping was used to study the membrane potential of the right atrium in Langendorff perfused Dct^-/- (n = 9) and Dct^+/- (n = 9) mice. Results Apamin prolonged action potential duration (APD) by 18.8 ms (95% confidence interval [CI] 13.4-24.1 ms) in Dct^-/- mice and by 11.5 ms (95% CI 5.4-17.6 ms) in Dct^+/- mice at a pacing cycle length of 150 ms (P =.047). The pacing cycle length threshold to induce APD alternans was 48 ms (95% CI 34-62 ms) for Dct^-/- mice and 21 ms (95% CI 12-29 ms) for Dct^+/- mice (P =.002) at baseline, and it was 35 ms (95% CI 21-49 ms) for Dct^-/- mice and 22 ms (95% CI 11-32 ms) for Dct^+/- mice (P =.025) after apamin administration. Apamin prolonged post-burst pacing APD by 8.9 ms (95% CI 3.9-14.0 ms) in Dct^-/- mice and by 1.5 ms (95% CI 0.7-2.3 ms) in Dct^+/- mice (P =.005). Immunoblot and quantitative polymerase chain reaction analyses showed that protein and transcripts levels of SK1 and SK3 were increased in the right atrium of Dct^-/- mice. AA inducibility (89% vs 11%; P =.003) and duration (281 seconds vs 66 seconds; P =.008) were greater in Dct^-/- mice than in Dct^+/- mice at baseline, but not different (22% vs 11%; P = 1.00) after apamin administration. Five of 8 (63%) induced atrial fibrillation episodes in Dct^-/- mice had focal drivers. Conclusion Apamin-sensitive SK current upregulation in Dct^-/- mice plays an important role in the mechanism of AA.