Effects of flecainide and quinidine on Kv4.2 currents: voltage dependence and role of S6 valines

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Abstract
The effects of flecainide and quinidine were studied on wild‐type Kv4.2 channels (Kv4.2WT), channels with deletion of the N‐terminal domain (N‐del) and channels with mutations in the valine residues located at positions 402 and 404 in the presence (V[402,404]I) or in the absence (N‐del/V[402,404]I) of the N‐terminus. The experiments were performed at 37°C on COS7 cells using the whole‐cell configuration of the patch‐clamp technique. Flecainide and quinidine inhibited Kv4.2WT currents in a concentration‐dependent manner (IC50=23.6±1.1 and 12.0±1.4 μMat +50 mV, respectively), similar to their potency for the rest of the constructs at the same voltage. In Kv4.2WT channels, flecainide‐ and quinidine‐induced block increased as channel inactivation increased. In addition, the inhibition produced by quinidine, but not by flecainide, increased significantly at positive test potentials. Similar effects were observed in N‐del channels. However, in V[402,404]I and N‐del/V[402,404]I channels, the voltage dependence of block by both quinidine and flecainide was lost, without significant modifications in potency at +50 mV. These results point to an important role for S6 valines at positions 402 and 404 in mediating voltage‐dependent block by quinidine and flecainide. British Journal of Pharmacology (2003) 138, 1475–1484. doi:10.1038/sj.bjp.0705199