HERG, a Human Inward Rectifier in the Voltage-Gated Potassium Channel Family

Trudeau, Matthew C.; Warmke, Jeffrey W.; Ganetzky, Barry; Robertson, Gail A.

doi:10.1126/science.7604285

Cited by 1,157 publications

(1,036 citation statements)

References 32 publications

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“…The I HERG tail amplitude exceeds current magnitude during voltage commands to positive voltages due to the particularly rapid voltagedependent inactivation kinetics of HERG channels (Sanguinetti et al, 1995;Trudeau et al, 1995;Smith et al, 1996;Zhou et al, 1998). Both the current during the pulse and the ensuing I HERG tail on repolarization to 740 mV were inhibited by the drug.…”

Section: Concentration-dependent Inhibition Of I Herg By Flecmentioning

confidence: 99%

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

Paul¹,

Witchel²,

Hancox³

2002

British J Pharmacology

148

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1 The inhibition of the cardiac`rapid' delayed recti®er current (I Kr ) and its cloned equivalent HERG mediate QT interval prolonging e ects of a wide range of clinically used drugs. In this study, we investigated the e ects of the Class Ic antiarrhythmic agent¯ecainide (FLEC) on ionic current (I HERG ) mediated by cloned HERG channels at 378C . We also compared the inhibitory potency of FLEC with other Class I agents: quinidine (QUIN, Class Ia); lignocaine (LIG, Class Ib) and propafenone (PROPAF, Class Ic). 2 Whole cell voltage clamp recordings of I HERG were made from an HEK293 cell line stably expressing HERG. FLEC inhibited I HERG`t ails' following test pulses to +30 mV with an IC 50 of 3.91+0.68 mM (mean+s.e.mean) and a Hill co-e cient close to 1 (0.76+0.09).3 In experiments in which I HERG tails were monitored following voltage commands to a range of test potentials, I HERG inhibition by FLEC was observed to be voltage-dependent and to be associated with a *75 mV shift of the activation curve for the current. Voltage-dependence of inhibition was greatest over the range of potentials corresponding to the steep portion of the I HERG activation curve. The time-course of I HERG tail deactivation was not signi®cantly altered by FLEC. 4 In experiments in which 10 s depolarizing pulses were applied from 780 to 0 mV, the level of current inhibition by FLEC did not increase between 1 and 10 s. Some time-dependence of inhibition was observed during the ®rst 200 ± 300 ms of depolarization. This observation and the voltage-dependence of inhibition are collectively consistent with FLEC exerting a rapid open channel state inhibition of I HERG . 5 Under similar recording conditions QUIN inhibited I HERG with an IC 50 of 0.41+0.04 mM and PROPAF inhibited I HERG with an IC 50 of 0.44+0.07 mM. Similar to FLEC, both QUIN and PROPAF showed voltage-dependence of inhibition and blockade developed rapidly during a sustained depolarization. 6 LIG showed little e ect on I HERG at low micromolar concentrations, but could inhibit the current at higher concentrations; the observed IC 50 was 262.90+22.40 mM. 7 Our data are consistent with FLEC, PROPAF and QUIN exerting I HERG blockade at clinically relevant concentrations. The rank potency as HERG blockers of the Class I drugs tested in this study was QUIN=PROPAF4FLEC44LIG. British Journal of Pharmacology (2002) 136, 717 ± 729 Keywords: Antiarrhythmic; Class Ia; Class Ib; Class Ic;¯ecainide; HERG; I Kr ; QT interval; QT prolongation; quinidine Abbreviations: ANOVA, analysis of variance; d, fractional distance in the transmembrane ®eld sensed at drug receptor site; DISO, disopyramide; FLEC,¯ecainide; HERG, Human ether-a-go-go related gene; IC 50 , half maximal inhibitory drug concentration; I Ca,L , L-type calcium current; I HERG , current mediated by the HERG channel; I K , delayed recti®er potassium current; I Kr`r apid' delayed recti®er potassium current; I Ks`s low' delayed recti®er potassium current; I to , transient outward potassium current; k, slope factor describing voltage de...

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Section: Concentration-dependent Inhibition Of I Herg By Flecmentioning

confidence: 99%

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

Paul¹,

Witchel²,

Hancox³

2002

British J Pharmacology

148

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“…Human ether à go-go related gene (hERG) K + channels mediate the rapidly activating I Kr current in cardiac myocytes and play a pivotal role in the termination of the cardiac action potential [1][2][3][4]. Defects in the hERG1 gene or pharmacological interventions that alter the hERG1 channel properties can give rise to inherited (long QT-syndrome 2) or acquired cardiac arrhythmias, respectively [3,[5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Functional consequences of methionine oxidation of hERG potassium channels

Limberis

Martin

et al. 2007

Biochemical Pharmacology

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Reactive species oxidatively modify numerous proteins including ion channels. Oxidative sensitivity of ion channels is often conferred by amino acids containing sulfur atoms, such as cysteine and methionine. Functional consequences of oxidative modification of methionine in hERG1 (human ether à go-go related gene 1), which encodes cardiac I Kr channels, are unknown. Here we used chloramine-T (ChT), which preferentially oxidizes methionine, to examine the functional consequences of methionine oxidation of hERG channels stably expressed in a human embryonic kidney cell line (HEK 293) and native hERG channels in a human neuroblastoma cell line (SH-SY5Y). ChT (300 µM) significantly decreased whole-cell hERG current in both HEK 293 and SH-SY5Y cells. In HEK 293 cells, the effects of ChT on hERG current were time-and concentration-dependent, and were markedly attenuated in the presence of enzyme methionine sulfoxide reductase A that specifically repairs oxidized methionine. After treatment with ChT, the channel deactivation upon repolarization to −60 or −100 mV was significantly accelerated. The effect of ChT on channel activation kinetics was voltage-dependent; activation slowed during depolarization to +30 mV but accelerated during depolarization to 0 or −10 mV. In contrast, the reversal potential, inactivation kinetics, and voltage-dependence of steady-state inactivation remained unaltered. Our results demonstrate that the redox status of methionine is an important modulator of hERG channel.

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“…2,3 The gene encodes the α-subunit of an inwardly rectifying K + channel, 4 and in the heart, this is an important constituent of a rapid delayed rectifier current, I Kr , that regulates cardiac action potential repolarization. 2,[5][6][7] Long QT syndrome (LQTS) is characterized by prolongation of the QT interval in the electrocardiogram resulting from a slow repolarization of cardiac action potentials and is associated with a serious multifocal ventricular arrhythmia, torsades de pointes.…”

Section: Introductionmentioning

confidence: 99%

Rb+ Flux through hERG Channels Affects the Potency of Channel Blocking Drugs: Correlation with Data Obtained Using a High-Throughput Rb+ Efflux Assay

Rezazadeh¹,

Hesketh²,

Fedida³

2004

SLAS Discovery

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The nonradioactive Rb+ efflux assay has become a reliable and efficient high-throughput hERG screening method, but it is limited by its low sensitivity for potent hERG blockers. Using the patch clamp technique, the authors found that the low sensitivity is due in part to the use of Rb+ as the permeating cation in the assay. The affinities of the drugs measured by patch clamp technique in the presence of Rb+ were 3- to 10-fold lower than when measured by the same method in the presence of K+ ions. The apparent affinity of the drugs decreased even further when monitored bytheRb+ efflux assay. It was also observed that Rb+ had minimal effects on the activation properties of channels while there was a significant change in the half-inactivation potential. This voltage shift reduces hERG channel inactivation at efflux assay potentials, and will reduce the affinity of hERG-blocking drugs that bind to inactivated states of the channel. In combination with the effects of elevated extracellular ion concentrations, it is likely that Rb+ modulation of hERG channel inactivation is largely responsible for the reduced drug potencies observed in the Rb+ efflux assay.

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HERG, a Human Inward Rectifier in the Voltage-Gated Potassium Channel Family

Cited by 1,157 publications

References 32 publications

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

Functional consequences of methionine oxidation of hERG potassium channels

Rb+ Flux through hERG Channels Affects the Potency of Channel Blocking Drugs: Correlation with Data Obtained Using a High-Throughput Rb+ Efflux Assay

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