Abstract
Background: Small-conductance Ca2+-activated K+ channels (SK channels) have been proposed as antiarrhythmic targets for the treatment of atrial fibrillation. We previously demonstrated that the 5-HT3 receptor antagonist ondansetron inhibits heterologously expressed, human SK2 (hSK2) currents as well as native cardiac SK currents in a physiological extra-/intracellular [K+] gradient at therapeutic (i.e., sub-micromolar) concentrations. A recent study, using symmetrical [K+] conditions, challenged this result. The goal of the present study was to revisit the inhibitory effect of ondansetron on hSK2-mediated currents in symmetrical [K+] conditions. Experimental Approach: The whole-cell patch clamp technique was used to investigate the effects of ondansetron and apamin on hSK2-mediated currents expressed in HEK 293 cells. Currents were measured in symmetrical [K+] conditions in the presence of 100 nM [Ca2+]o. Results: Expression of hSK2 produced inwardly rectifying whole-cell currents in the presence of 400 nM free cytosolic Ca2+. Ondansetron inhibited whole-cell hSK2 currents with IC 50 values of 154 and 113 nM at −80 and 40 mV, respectively. Macroscopic current inhibited by ondansetron and current inhibited by apamin exhibited inwardly rectifying current-voltage relationships with similar reversal potentials (apamin, ∼5 mV and ondansetron, ∼2 mV). Ondansetron (1 μM) in the continuing presence of apamin (100 nM) had no effect on hSK2-mediated whole-cell currents. Wild-type HEK 293 cells did not express ondansetron- or apamin-sensitive currents. Conclusion: Ondansetron in sub-micromolar concentrations inhibits hSK2 currents even under altered ionic conditions.
Highlights
Small-conductance Ca2+-activated K+ channels (SK channels) have been proposed as antiarrhythmic targets for the treatment of atrial fibrillation (Heijman and Dobrev, 2017; Ravens and Odening, 2017)
Since ionic conditions for human SK2 (hSK2) current measurements that Kirchhoff et al used were different from those used in our previous experiments, the goal of the present study was to re-evaluate the efficacy of ondansetron in inhibiting hSK2-mediated currents expressed in human embryonic kidney (HEK) 293 cells under ionic conditions replicating those employed by Kirchhoff et al Our results indicate that ondansetron retains its inhibitory effect on hSK2 channels even under altered ionic conditions
These data suggest that there is no detectable expression of apamin- or ondansetron-sensitive currents in wild type HEK 293 cells used in the present study
Summary
Small-conductance Ca2+-activated K+ channels (SK channels) have been proposed as antiarrhythmic targets for the treatment of atrial fibrillation (Heijman and Dobrev, 2017; Ravens and Odening, 2017). We previously demonstrated that the 5-HT3 receptor antagonist ondansetron, a widely prescribed antiemetic, blocks heterologously expressed, human SK2 (hSK2) channels at therapeutic (i.e., sub-micromolar) concentrations (Ko et al, 2018), suggesting its possible repurpose as an atrial-selective antiarrhythmic drug. Since ionic conditions for hSK2 current measurements that Kirchhoff et al used (symmetrical [K+], presence of extracellular Ca2+) were different from those used in our previous experiments (physiological extra-/ intracellular [K+] gradient, absence of extracellular Ca2+), the goal of the present study was to re-evaluate the efficacy of ondansetron in inhibiting hSK2-mediated currents expressed in HEK 293 cells under ionic conditions replicating those employed by Kirchhoff et al Our results indicate that ondansetron retains its inhibitory effect on hSK2 channels even under altered ionic conditions. Currents were measured in symmetrical [K+] conditions in the presence of 100 nM [Ca2+]o
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