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]I) or in the absence (N-del/V[402,404]I) of the N-terminus. 2. The experiments were performed at 37 degrees C 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 (IC(50)=23.6+/-1.1 and 12.0+/-1.4 microMat +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. 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.
Department of Pharmacology, School of Medicine, Universidad Complutense, Madrid, Spain.
Ricardo
R
Caballero
Marc
M
Pourrier
Gernot
G
Schram
Eva
E
Delpón
Juan
J
Tamargo
Stanley
S
Nattel
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D005424:Flecainide / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009154:Mutation / Q000502:physiology; D015221:Potassium Channels / Q000502:physiology*; D024642:Potassium Channels, Voltage-Gated; D011802:Quinidine / Q000494:pharmacology*; D051381:Rats; D051672:Shal Potassium Channels; D014633:Valine / Q000502:physiology*
D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D051672:Shal Potassium Channels; D014633:Valine; D011802:Quinidine; D005424:Flecainide