Class III Antiarrhythmic Drugs Block HERG, a Human Cardiac Delayed Rectifier K ⁺ Channel

Abstract

We recently reported that mutations in HERG, a potassium channel gene, cause long QT syndrome. Heterologous expression of HERG in Xenopus oocytes revealed that this channel had biophysical properties nearly identical to a cardiac delayed rectifier K+ current I(Kr), but had dissimilar pharmacological properties. Class III antiarrhythmic drugs such as E-4031 and MK-499 are potent and specific blockers of I (Kr) in cardiac myocytes. Our initial studies indicated that these compounds did not block HERG at a concentration of 1 micromol/L. In the present study, we used standard two-microelectrode voltage-clamp techniques to further characterize the effects of these drugs on HERG channels expressed in oocytes. Consistent with initial findings, 1 micromol/L MK-499 and E-4031 had not effect on HERG when oocytes were voltage clamped at a negative potential and not pulsed during equilibration with the drug. However, MK-499 did block HERG current if oocytes were repetitively pulsed, or clamped at a voltage positive to the threshold potential for channel activation. This finding is in contrast to previous studies that showed significant block of I(Kr) in isolated myocytes by similar drugs, even in the absence of pulsing. This apparent discrepancy may be due to differences in channel characteristics (HERG versus guinea pig and mouse I (Kr)), tissue (oocytes versus myocytes), or specific drugs. Under steady state conditions, block of HERG by MK-499 was half maximal at 123 +/- 12 nmol/L at a test potential of -20 mV. MK-499 (150 nmol/L) did not affect the voltage dependence of activation and rectification nor the kinetics of activation and deactivation of HERG. These data indicate that MK-499 preferentially blocks open HERG channels and further support the conclusion that HERG subunits form I(Kr) channels in cardiac myocytes.

Open Channel Block by KCB-328 [1-(2-Amino-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane Hydrochloride] of the Heterologously Expressed HumanEther-a-go-go-Related Gene K+ Channels

“…It also prolonged APD and inhibited I K (Lee et al, 1998). It is well known that heterologously expressed HERG currents share pharmacological and biophysical properties with I Kr (Kiehn et al, 1995;Sanguinetti et al, 1995;Spector et al, 1996;Wang et al, 1997). The characteristics of the current recorded in the present study correspond to HERG current: slow current activation at negative potentials, large, long-lasting tail currents on repolarization, strong inward rectification and sensitivity to class III methanesulfonanilides such as MK-499 and dofetilide.…”

“…Interestingly, naturally occurring mutations in HERG underlie the chromosome 7-linked inherited long QT syndrome (LQT) Sanguinetti et al, 1995). Heterologously expressed HERG currents share pharmacological properties with I Kr and are blocked by methanesulfonanilides such as dofetilide and MK-499 (Kiehn et al, 1995;Spector et al, 1996). I Kr /HERG represents an important target for antiarrhythmic drugs.…”

APETx1, a New Toxin from the Sea AnemoneAnthopleura elegantissima, Blocks Voltage-Gated HumanEther-a-go-go–Related Gene Potassium Channels

“…Because drugs such as class III antiarrhythmic agents preferentially block open HERG channels (Snyders and Chaudhary, 1996;Spector et al, 1996), we compared the use dependence of the current inhibition by the toxin under repetitive pulses at 0 mV from a holding potential of Ϫ80 mV using pulse intervals of either 1 or 10 s. The steady-state of inhibition by APETx1 (50 nM) was obtained within 101 Ϯ 19 s (n ϭ 6) and 64 Ϯ 13 s (n ϭ 11, values are significantly different, P ϭ 0.0003) during depolarization pulses every 1 and 10 s, respectively (Fig. 6C).…”

“…HERG channels are essential in cardiac cells, where they control the duration of the plateau phase of the action potential. Several mutations on the HERG gene are responsible for inherited disorders characterized by abnormal, slow repolarization of action potentials associated with long QT intervals on electrocardiograms Spector et al, 1996). This long QT syndrome causes episodic ventricular arrhythmias and ventricular fibrillation, which can result in syncope and sudden death.…”

Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs

“…Block of hERG K ϩ channels by most drugs requires opening of the activation gate, indicating that compounds bind within the inner cavity (Spector et al, 1996;Mitcheson et al, 2000b). Available evidence suggests hERG has a relatively large inner cavity compared with the K V channel family (Mitcheson et al, 2000b;Mitcheson and Perry, 2003).…”