Abstract
The natural flavone acacetin inhibits several voltage-gated potassium currents in atrial myocytes, and has anti-atrial fibrillation (AF) effect in experimental AF models. The present study investigates whether acacetin inhibits the Ca2+-activated potassium (KCa) currents, including small conductance (SKCa1, SKCa2, and SKCa3), intermediate conductance (IKCa), and large-conductance (BKCa) channels stably expressed in HEK 293 cells. The effects of acacetin on these KCa channels were determined with a whole-cell patch voltage-clamp technique. The results showed that acacetin inhibited the three subtype SKCa channel currents in concentration-dependent manner with IC50 of 12.4 μM for SKCa1, 10.8 μM for SKCa2, and 11.6 μM for SKCa3. Site-directed mutagenesis of SKCa3 channels generated the mutants H490N, S512T, H521N, and A537V. Acacetin inhibited the mutants with IC50 of 118.5 μM for H490N, 275.2 μM for S512T, 15.3 μM for H521N, and 10.6 μM for A537V, suggesting that acacetin interacts with the P-loop helix of SKCa3 channel. However, acacetin at 3–10 μM did not decrease, but induced a slight increase of BKCa (+70 mV) by 8% at 30 μM. These results demonstrate the novel information that acacetin remarkably inhibits SKCa channels, but not IKCa or BKCa channels, which suggests that blockade of SKCa by acacetin likely contributes to its anti-AF property previously observed in experimental AF.
Highlights
Potassium channels are the largest and the most diverse super-family of ion channels in living organisms from bacteria and insects to animals including humans
Our results showed that acacetin inhibited the three subtypes of small conductance Ca2+activated potassium channels (SKCa) channels, but not intermediate conductance Ca2+-activated potassium channels (IKCa) and big/large conductance Ca2+-activated potassium channels (BKCa) channels, suggesting that the blockade of SKCa channels may participate in the anti-atrial fibrillation (AF) previously observed in experimental canine models
The present study provides the novel information that the natural flavone acacetin blocks the three SKCa channel subtypes: SKCa1, SKCa2, and SKCa3, stably expressed in HEK 293 cells with similar efficacy
Summary
Potassium channels are the largest and the most diverse super-family of ion channels in living organisms from bacteria and insects to animals including humans. Ca2+-activated potassium channels (KCa) comprise many members. They are divided into three subfamilies: big (or large) conductance (BKCa, Slo, or KCa1.1, encoded by KCNMA1), intermediate conductance. A recent report demonstrated that the SKCa inhibitor apamin may cause ventricular arrhythmias in failing rabbit hearts (Chang et al, 2013); blockade of SKCa channels is very effective in anti-AF (Diness et al, 2010; Qi et al, 2014; Haugaard et al, 2015). The development of SK channel blockers has been considered as a new therapeutic strategy in the treatment of AF (Zhang et al, 2015)
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