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

Abstract

Background The melanin synthesis enzyme dopachrome tautomerase (Dct) regulates intracellular Ca2+ in melanocytes. Homozygous Dct knock out (Dct−/−) adult mice are vulnerable to atrial arrhythmias (AA). Objective To determine if apamin-sensitive small conductance Ca2+ activated K+ currents (IKAS) are upregulated in Dct−/− mice and contribute to AA. Methods Optical mapping was used to study the membrane potential of right atria (RA) 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) in Dct−/− and by 11.5 ms (CI, 5.4–17.6) in Dct+/− mice at 150 ms PCL (p= 0.047). PCL threshold to induce APD alternans was 48 ms (CI, 34–62) for Dct−/− and 21 ms (CI, 12–29) for Dct+/− mice (p=0.002) at baseline, versus 35 ms (CI, 21–49) for Dct−/− and 22 ms (CI, 11–32) for Dct+/− mice (p=0.025) after apamin. Apamin prolonged post-burst pacing APD by 8.9 ms (CI, 3.9–14.0) in Dct−/− and by 1.5 ms (CI, 0.7–2.3) in Dct+/− mice (p=0.005). Immunoblot and quantitative PCR analysis showed that protein and transcripts levels of SK1 and SK3 were increased in the RA of Dct−/− mice. AA inducibility (89% vs. 11%, p=0.003) and duration (281 sec vs. 66 sec, p=0.008) were greater in Dct−/− than in Dct+/− mice at baseline, but not different (22% vs 11%, p=1.00) after apamin. Five of 8 (63%) induced AF episodes in Dct−/− mice had focal drivers. Conclusion IKAS upregulation in Dct−/− mice plays an important role in the mechanism of AA.

Ondansetron blocks wild-type and p.F503L variant small-conductance Ca2+-activated K+ channels

“…The first potential clinical implication is that ondansetron may be useful as an antiarrhythmic agent. Previous studies in animal models have shown that apamin is potentially useful in the management of electrical storm (7) and atrial fibrillation (6,24,26). However, because apamin is a neurotoxin, it cannot be used as a drug for humans.…”

Arrhythmogenic calmodulin mutations impede activation of small-conductance calcium-activated potassium current

“…28 Enhanced L-type Ca 2+ current and aberrant ryanodine receptor type 2 regulation are among the dominant mechanisms responsible for cardiac arrhythmogenesis. 29, 30 Prior studies showed that SK currents are upregulated in pathogenic conditions while SK current blockade may be proarrhythmic, 10, 31 suggesting that SK current upregulation is a physiological response to reduced repolarization reserve and that SK current blockade might be arrhythmogenic in certain clinical conditions. 32 The data obtained in our present study suggest that mutant calmodulin impedes the activation of SK current, which may play a role in the arrhythmic phenotypes experienced by patients with calmodulin mutations.…”

Differential regulation of K Ca 2.1 ( KCNN1 ) K + channel expression by histone deacetylases in atrial fibrillation with concomitant heart failure

“…HF‐related atrial arrhythmogenesis is characterized by decreased atrial K + currents, resulting in prolongation of atrial APD and AERP (Lugenbiel et al, 2017; Schmidt et al, 2017). Reduced K Ca channel expression and function in AF may contribute to this electrophysiological hallmark of AF/HF patients (Diness et al, 2010; Li et al, 2009; Ozgen et al, 2007; Qi et al, 2014; Skibsbye et al, 2014; Tsai et al, 2016; Zhang, Timofeyev, et al, 2014). Reversal of K Ca 2.1 channel remodeling could represent an individualized strategy for rhythm control in this specific AF patient entity.…”