The inward rectification mechanism of the HERG cardiac potassium channel

Smith, Paula; Baukrowitz, Thomas; Yellen, Gary

doi:10.1038/379833a0

Cited by 722 publications

(875 citation statements)

References 22 publications

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“…The correction factor was calculated for each test pulse at negative potentials where the current declined because of channel closure. The corrected current at the return step (+20 mV) was plotted as a function of voltage of the 20-ms test pulses to obtain the steady-state inactivation curve [27,31,32]. Peak current amplitudes at the return step to +20 mV were prominently decreased by ChT (300 µM), consistent with the results presented thus far.…”

Section: Effect Of Cht On Voltage Dependence and Kinetics Of Herg Chasupporting

confidence: 83%

“…Despite the increasing evidence that oxidation of Met and its repair by MSRs modulate ion channel function and cellular electrical excitability, whether oxidation of Met has any functional consequence in hERG1 channels with fast P/C-type inactivation [27,28] is not known. Thus we investigated if these K + channels undergo functional changes in response to treatments that promote Met oxidation.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Effect Of Cht On Voltage Dependence and Kinetics Of Herg Chasupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Functional consequences of methionine oxidation of hERG potassium channels

Limberis

Martin

et al. 2007

Biochemical Pharmacology

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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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“…I Kr is named as such because it is rapidly activating and the currents are characteristically inwardly rectifying due to its unique inactivation properties [62]. I Kr is composed of hERG (human ether-a-go-go related gene) and possibly a β subunit of the KCNE family though this is still controversial [63,64].…”

Section: Repolarising Currentsmentioning

confidence: 99%

Potassium channels in the sinoatrial node and their role in heart rate control

Aziz

Tinker

2018

Channels

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Potassium currents determine the resting membrane potential and govern repolarisation in cardiac myocytes. Here, we review the various currents in the sinoatrial node focussing on their molecular and cellular properties and their role in pacemaking and heart rate control. We also describe how our recent finding of a novel ATP-sensitive potassium channel population in these cells fits into this picture.

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The inward rectification mechanism of the HERG cardiac potassium channel

Cited by 722 publications

References 22 publications

Functional consequences of methionine oxidation of hERG potassium channels

Functional consequences of methionine oxidation of hERG potassium channels

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

Potassium channels in the sinoatrial node and their role in heart rate control

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