AUTHOR=Guo Shuai , Chen Zhenhui , Chen Peng-Sheng , Rubart Michael TITLE=Inhibition of Small-Conductance, Ca2+-Activated K+ Current by Ondansetron JOURNAL=Frontiers in Pharmacology VOLUME=12 YEAR=2021 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.651267 DOI=10.3389/fphar.2021.651267 ISSN=1663-9812 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 IC₅₀ 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.