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

1 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]1) or in the absence (N-del/ V[402,404]1) of the N-terminus. 2 The experiments were performed at 37degreesC on COS7 cells using the whole-cell configuration of the patch-clamp technique. 3 Flecainide and quinidine inhibited Kv4.2WT currents in a concentration-dependent manner (IC50 = 23.6 +/- 1.1 and 12.0 +/- 1.4 muM at + 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]1 channels, the voltage dependence of block by both quinidine and flecainide was lost, without significant modifications in potency at + 50 mV. 4 These results point to an important role for S6 valines at positions 402 and 404 in mediating voltage-dependent block by quinidine and flecainide.