Molecular Site of Action of the Antiarrhythmic Drug Propafenone at the Voltage-Operated Potassium Channel Kv2.1

Abstract

The effects of the antiarrhythmic drug propafenone at Kv2.1 channels were studied with wild-type and mutated channels expressed in Xenopus laevis oocytes. Propafenone decreased the Kv2.1 currents in a time-and voltage-dependent manner (decrease of the time constants of current rise, increase of block with the duration of voltage steps starting from a block of less than 19%, increase of block with the amplitude of depolarization yielding a fractional electrical distance ␦ of 0.11 to 0.16). Block of Kv2.1 appeared with application to the intracellular, but not the extracellular, side of membrane patches. In mutagenesis experiments, all parts of the Kv2.1 channel were successively exchanged with those of the Kv1.2 channel, which is much more sensitive to propafenone. The intracellular amino and carboxyl terminus and the intracellular linker S4-S5 reduced the blocking effect of propafenone, whereas the linker S5-S6, as well as the segment S6 of the Kv1.2 channel, abolished it to the value of the Kv1.2 channel. In the linker S5-S6, this effect could be narrowed down to two groups of amino acids (groups 372 to 374 and 383 to 384), which also affected the sensitivity to tetraethylammonium. In segment S6, several amino acids in the intracellularly directed part of the helix significantly reduced propafenone sensitivity. The results suggest that propafenone blocks the Kv2.1 channel in the open state from the intracellular side by entering the inner vestibule of the channel. These results are consistent with a direct interaction of propafenone with the lower part of the pore helix and/or residues of segment S6.

Auranofin Protects against Anthrax Lethal Toxin-Induced Activation of the Nlrp1b Inflammasome

“…We selected the inhibitors flecainide (Kv1.3 channel inhibitor), loratadine (Kv1.5 channel inhibitor), propafenone (Kv2.1 channel inhibitor), and broadly acting quinidine (Kv1.5 and other channels) (13,15,25,31,45). The calculated combination indices for these drugs are shown in Table 1.…”

Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes

“…Propafenone inhibits several channels, especially the voltage-gated sodium channel SCN5A and the voltage-gated potassium channel KCNH2 (29). Propafenone also inhibits ATPsensitive potassium channel (K ATP ) currents in myocytes (32) and vascular smooth muscle (33), and the delayed rectifier channel Kv2.1 in Xenopus oocytes (34). Decreased activity of K ATP or Kv2.1 in islets increases insulin secretion (19), suggesting that these channels may mediate propafenone's effects on insulin secretion.…”

Effects of diltiazem and propafenone on the inactivation and recovery kinetics of fKv1.4 channel currents expressed in Xenopus oocytes

“…The L-type calcium channel blocker diltiazem and the sodium channel blocker propafenone have been reported to block several cloned potassium channels, including Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv2.1, Kv4.2, and hERG channel currents [16,[21][22][23][24] . For instance, diltiazem, at concentrations of 0.01 nmol/L to 500 μmol/L, suppressed the hKv1.5 potassium channel expressed in mouse fibroblasts with an estimated IC 50 of 42.3 μmol/L [17] .…”

“…The construction of fKv1.4ΔN was performed by removal of 2-146 amino acid residues from the N-terminal domain of Kv1. 4, which results in the loss of the fast component of inactivation but leaves the C-type inactivation pathway intact [19][20][21] . Transcribed fKv1.4ΔN cRNA was prepared in vitro using an mMessage mMachine kit (T3 kit, Ambion, USA).…”

“…The constructs and sequences of the cDNA fKv1.4ΔN used in this study have been previously described [19][20][21] and were a gift from professor Randall L RASMUSSON (University at Buffalo, SUNY). The construction of fKv1.4ΔN was performed by removal of 2-146 amino acid residues from the N-terminal domain of Kv1.…”