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PubMed1999

Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes.

The high incidence of sudden death in heart failure may reflect abnormalities of repolarization and heightened susceptibility to arrhythmogenic early afterdepolarizations (EADs). We hypothesized that overexpression of the human K+ channel HERG (human ether-a-go-go-related gene) could enhance repolarization and suppress EADs. Adult rabbit ventricular myocytes were maintained in primary culture, which suffices to prolong action potentials and predisposes to EADs. To achieve efficient gene transfer, we created AdHERG, a recombinant adenovirus containing the HERG gene driven by a Rous sarcoma virus (RSV) promoter. The virally expressed HERG current exhibited pharmacologic and kinetic properties like those of native IKr. Transient outward currents in AdHERG-infected myocytes were similar in magnitude to those in control cells, while stimulated action potentials (0.2 Hz, 37 degrees C) were abbreviated compared with controls. The occurrence of EADs during a train of action potentials was reduced by more than fourfold, and the relative refractory period was increased in AdHERG-infected myocytes compared with control cells. Gene transfer of delayed rectifier potassium channels represents a novel and effective strategy to suppress arrhythmias caused by unstable repolarization.

Action Potentials↗
PubMed2001

High-affinity blockade of human ether-a-go-go-related gene human cardiac potassium channels by the novel antiarrhythmic drug BRL-32872.

Human ether-a-go-go-related gene (HERG) potassium channels are one primary target for the pharmacological treatment of cardiac arrhythmias by class III antiarrhythmic drugs. These drugs are characterized by high antiarrhythmic efficacy, but they can also initiate life-threatening "torsade de pointes" tachyarrhythmias. Recently, it has been suggested that combining potassium and calcium channel blocking mechanisms reduces the proarrhythmic potential of selective class III antiarrhythmic agents. BRL-32872 is a novel antiarrhythmic drug that inhibits potassium and calcium currents in isolated cardiomyocytes. In our study, we investigated the effects of BRL-32872 on cloned HERG channels heterologously expressed in Xenopus oocytes. Using the two-microelectrode voltage clamp technique, we found that BRL-32872 caused a high-affinity, state-dependent block of open HERG channels (IC(50) = 241 nM) in a frequency-dependent manner with slow unbinding kinetics. Inactivated channels mainly had to open to be blocked by BRL-32872. The HERG S620T mutant channel, which has a strongly reduced degree of inactivation, was 51-fold less sensitive to BRL-32872 block, indicating that BRL-32872 binding was enhanced by the inactivation process. In an additional approach, we studied HERG channels expressed in a human cell line (HEK 293) using the whole-cell patch-clamp technique. BRL-32872 inhibited HERG currents in HEK 293 cells in a dose-dependent manner, with an IC(50) value of 19.8 nM. We conclude that BRL-32872 is a potent blocker of HERG potassium channels, which accounts for the class III antiarrhythmic action of BRL-32872.

Animals↗
PubMed2005

Inhibitory effect of rhynchophylline on human ether-a-go-go related gene channel.

We studied the effects of Chinese traditional medicine rhynchophylline (Rhy) on human ether-a-go-go related gene (HERG) channel and characterized the electrophysiological properties of Rhy's pharmacological effect on HERG channel using Xenopus oocytes. Xenopus oocytes were injected with either 23 nl (5.75 ng) HERG cRNA or 23 nl distilled water. Xenopus oocytes were randomly assigned to receive one of the following different concentrations of Rhy: (1) control, (2)10 mumol/L Rhy, (3)100 mumol/L Rhy, (4) 500 mumol/L Rhy, (5) 1 000 mumol/L Rhy, (6) 10 000 mumol/L Rhy. Cell currents were recorded in oocytes. The peak tail currents of HERG channel were inhibited by Rhy. The inhibition was in a dose-dependent manner [IC(50)=(773.4 +/- 42.5) mumol/L]. Experiment with 100 mumol/L Rhy indicated that the degree of HERG blockade showed some voltage dependence (within -40 mV to -20 mV ). Kinetic analyses revealed that Rhy decreased the rate of channel activation. The findings indicate that Rhy inhibits HERG encoded potassium channels. It may underline the molecular mechanism of myocardial electrophysiological characteristics associated with this drug.

Animals↗
PubMed2003

The HERG K+ channel: progress in understanding the molecular basis of its unusual gating kinetics.

The HERG K+ channel has very unusual kinetic behaviour that includes slow activation but rapid inactivation. These features are critical for normal cardiac repolarisation as well as in preventing lethal ventricular arrhythmias. Extensive mutagenesis of the HERG K+ channel has allowed identification of which regions of the channel are important for the unusual kinetic behaviour of the channel. Furthermore, structural studies on scorpion toxins that potently inhibit HERG are beginning to provide clues as to the structural differences between HERG and other voltage-gated K+ channels.

Amino Acid Sequence↗
PubMed2005

Effect of trazodone on hERG channel current and QT-interval.

Trazodone has been associated with prolonged QT-interval and increased risk of polymorphous ventricular tachycardias clinically and has demonstrated in vitro inhibition of hERG (human ether-á-go-go-related gene) channel current. This study attempts to put the effects of trazodone into perspective by comparing its hERG inhibition to that of three agents known to inhibit I(Kr), and comparing the effects of trazodone and cisapride on action potential duration and the QT-interval in the rabbit Langendorff heart preparation. Trazodone inhibited hERG channel current in a concentration-dependent manner with an IC50 of 0.69 microM. Like astemizole, terfenadine and cisapride, trazodone inhibits hERG channel current at clinically relevant concentrations. Like cisapride, trazodone increased both the QT-interval and APD90 in the Langendorff heart preparation in a reverse frequency-dependent manner at clinically relevant concentrations. These data strongly suggest that trazodone prolongs the QT-interval through inhibition of hERG channel current.

Action Potentials↗
PubMed2005

Tryptophan scanning mutagenesis of the HERG K+ channel: the S4 domain is loosely packed and likely to be lipid exposed.

Inherited mutations or drug-induced block of voltage-gated ion channels, including the human ether-à-go-go-related gene (HERG) K+ channel, are significant causes of malignant arrhythmias and sudden death. The fourth transmembrane domain (S4) of these channels contains multiple positive charges that move across the membrane electric field in response to changes in transmembrane voltage. In HERG K+ channels, the movement of the S4 domain across the transmembrane electric field is particularly slow. To examine the basis of the slow movement of the HERG S4 domain and specifically to probe the relationship between the S4 domain with the lipid bilayer and rest of the channel protein, we individually mutated each of the S4 amino acids in HERG (L524-L539) to tryptophan, and characterized the activation and deactivation properties of the mutant channels in Xenopus oocytes, using two-electrode voltage-clamp methods. Tryptophan has a large bulky hydrophobic sidechain and so should be tolerated at positions that interact with lipid, but not at positions involved in close protein-protein interactions. Significantly, we found that all S4 tryptophan mutants were functional. These data indicate that the S4 domain is loosely packed within the rest of the voltage sensor domain and is likely to be lipid exposed. Further, we identified residues K525, R528 and K538 as being the most important for slow activation of the channels.

Amino Acid Sequence↗
PubMed2006

Frequency-dependent modulation of KCNQ1 and HERG1 potassium channels.

To obtain information about a possible frequency-dependent modulation of HERG1 and hKCNQ1 channels, we performed heterologous expression in Xenopus laevis oocytes. Channel activation was obtained by voltage protocols roughly imitating cardiac action potentials at frequencies of 1, 3, 5.8, and 8.3Hz. The activity of HERG1 channels was inhibited down to 65% at high frequencies. In contrast, hKCNQ1 channel activity was increased up to 525% at high frequencies. The general frequency-dependent modulation of the channels was unaffected by both co-expression of hKCNQ1 and HERG1 channels, and by the presence of the beta-subunits KCNE1 and KCNE2. In addition, the functional role of HERG1 in native guinea pig cardiac myocytes was demonstrated at different pacing frequencies by application of 10microM of the new HERG1 activator, NS1643. In conclusion, we have demonstrated that HERG1 and hKCNQ1 channels are inversely modulated by stimulation frequency.

Action Potentials↗
PubMed2001

Long-QT syndrome-associated missense mutations in the pore helix of the HERG potassium channel.

BACKGROUND: Mutations in the human ether-à-go-go-related gene (HERG) cause chromosome 7-linked long-QT syndrome (LQTS), an inherited disorder of cardiac repolarization that predisposes affected individuals to arrhythmia and sudden death. METHODS AND RESULTS: Here, we characterize the physiological consequences of 3 LQTS-associated missense mutations (V612L, T613M, and L615V) located in the pore helix of the HERG channel subunit. Mutant HERG subunits were heterologously expressed in Xenopus oocytes alone or in combination with wild-type HERG subunits. Two-microelectrode voltage-clamp techniques were used to record currents, and a single oocyte chemiluminescence assay was used to assay surface expression of epitope-tagged subunits. When expressed alone, V612L and T613M HERG subunits did not induce detectable currents, and L615V induced very small currents. Coexpression of mutant and wild-type HERG subunits caused a dominant-negative effect that varied for each mutation. CONCLUSIONS: These findings define the physiological consequences of mutations in HERG that cause LQTS and indicate the importance of the pore helix of HERG for normal channel function.

Animals↗
PubMed1997

The seizure locus encodes the Drosophila homolog of the HERG potassium channel.

Mutations in the seizure (sei) locus cause temperature-induced hyperactivity, followed by paralysis. Gene cloning studies have established that the seizure gene product is the Drosophila homolog of HERG, a member of the eag family of K+ channels implicated in one form of hereditary long QT syndrome in humans. A series of five null alleles with premature stop codons are all recessive, but viable. A missense mutation in the sei gene, which changes the charge at a conserved glutamate residue near the outer mouth of the pore, has a semidominant phenotype, suggesting that the mutant seizure protein acts as a poison in a multimeric complex. Transformation rescue of a null allele with a cDNA under the control of an inducible promoter demonstrates that induced expression of seizure potassium channels in adults rescues the paralytic phenotype. This rescue decays with a t1/2 of approximately 1-1.5 d after gene induction is discontinued, providing the first estimate of ion channel stability in an intact, multicellular animal.

Amino Acid Sequence↗
PubMed1996

Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide.

BACKGROUND: The human ether-a-go-go-related gene (HERG) is one locus for the hereditary long-QT syndrome. A hypothesis is that HERG produces the repolarizing cardiac potassium current IKr with the consequence that mutations in HERG prolong the QT interval by reducing IKr. The elementary properties of HERG are unknown, and as a test of the hypothesis that HERG produces IKr, we compared their elementary properties. METHODS AND RESULTS: We injected HERG cRNA into Xenopus oocytes and measured currents from single channels or current variance from the noise produced by ensembles of channels recorded from macro patches. Single-channel conductance was dependent on the extracellular potassium concentration ([K]o). At physiological [K]o, it was 2 picosiemens (pS), and at 100 mmol/L [K]o, it was 10 pS. Openings occurred in bursts with a mean duration of 26 ms at -100 mV. Mean open time was 3.2 ms and closed times were 1.0 and 26 ms. In excised macro patches, HERG currents were blocked by the class III antiarrhythmic drug dofetilide, with an IC50 of 35 nmol/L. Dofetilide block was slow and greatly attenuated at positive potentials at which HERG rectifies. CONCLUSIONS: The microscopic physiology of HERG and IKr is similar, consistent with HERG being an important component of IKr. The pharmacology is also similar; dofetilide appears to primarily block activated channels and has a much lower affinity for closed and inactivated channels.

Animals↗
PubMed2002

The T wave as a marker of dispersion of ventricular repolarization in premature infants before and while on treatment with the I(Kr) channel blocker cisapride.

AIMS: Measurement of electrocardiographic intervals to assess dispersion in ventricular repolarization may be helpful in the assessment of the risk of ventricular arrhythmia. We measured QTc, QT dispersion, and T wave intervals in premature infants before and while on treatment with the I(Kr) blocker cisapride as markers for dispersion in ventricular repolarization. METHODS AND RESULTS: We enrolled 15 non-ventilated premature infants with a mean gestational age of 30.5 weeks, ranging from 26.5 to 33.5 weeks, and mean postnatal age of 24 days, with a range from 5 to 51 days. A digital 12 lead electrocardiogram was recorded prior to and 3 days after administering cisapride at a dose of 0.8 mg/kg/day. Serum electrolytes were simultaneously measured. Electrocardiographic measurements before and after included: QT, QTc Bazett, QT dispersion, R-R, T wave interval peak to end, T wave interval peak to end/onset Q to T wave peak, T wave axis, T wave maximum voltage and QRS-T angle. A paired t test and analysis of variance was used to compare the variables before and during treatment. The QTc, T wave interval peak to end and the ratio T wave interval peak to end/onset Q to T peak increased significantly following treatment with cisapride. Results expressed as before and during treatment were for QTc: 429 (65) ms versus 454 (29) ms p < 0.02; for T wave interval peak to end: 65 (11) ms versus 103 (24) p <0.01, for the ratio T wave interval peak to end/onset Q to T peak: 0.32 (0.06) versus 0.55 (0.16) p < 0.001. Treatment with the I(Kr) blocker did not significantly alter the QT dispersion, T wave voltage, angle or QRS-T angle. CONCLUSION: The interval from the peak to the end of the T wave and the ratio of this value to the onset Q to T peak interval, represents regional dispersion of repolarization across the ventricular wall. This is a potentially useful clinical index in the assessment of arrhythmic risk in premature infants being treated by blockade of the I(Kr) channels.

Belgium↗
PubMed2002

[Evaluation of pro-arrhythmic risk of drugs due to QT interval prolongation by the HERG expression system].

Recently, there has been considerable attention focused on drugs that prolong the QT interval of the electrocardiogram. This occasionally evolves to fetal, polymorphic ventricular arrhythmias, torsades de pointes. Therefore, the early detection of the risk of drug-induced QT prolongation is important for avoiding the adverse cardiovascular effect in clinical use. It has been suggested that the QT prolongation and ventricular arrhythmia caused by drugs might be secondary to their ability to interfere with cardiac potassium channels involved in action potential repolarization and in particular with rapidly activating delayed rectifier K+ current (IKr). In cardiac myocytes, IKr contributes to termination of the plateau phase of action potential. The ether-a-go-go related gene in humans expressed a K+ channel current with biophysical characteristics similar to those of IKr. Electrophysiological studies on cloned HERG channels can provide fundamental information concerning the cardiac safety profile of new developing drugs.

Animals↗
PubMed2001

Molecular cloning and expression of cERG, the ether à go-go-related gene from canine myocardium.

Given the anatomical and physiological similarities to the human heart, canine in vivo heart models may facilitate the analysis of molecular mechanisms underlying cardiac repolarization abnormalities. The development of such models depends, however, on information about canine K+ channels responsible for the establishment of IK currents. In this context, we isolated and sequenced the reverse transcript of the canine ether à go-go-related gene (cERG). The complementary deoxyribonucleic acid (cDNA-derived cERG polypeptide consists of 1,158 amino acids, the sequence of which shows striking homology to human, rat and mouse ERG subunits (97%, 94% and 95% identity respectively). In highly conserved peptide domains like the PAS domain, the membrane-spanning segments S1, S3-S6 and the pore-forming region, there was 100% identity. Analysis of cERG transcription revealed abundant expression of cERG messenger ribonucleic acid (mRNA) in heart and brain and low expression in liver, spleen and kidney. Membrane currents recorded in Xenopus oocytes expressing cERG channels showed functional properties very similar to the human K+ channel hERG, which encodes the alpha-subunit of the cardiac rapidly activating, delayed rectifier (IKr) channel.

Animals↗
PubMed2006

Effect of S5P alpha-helix charge mutants on inactivation of hERG K+ channels.

The ether-à-go-go (EAG) family of voltage-gated K(+) channels contains three subfamilies, EAG, ether-à-go-go related (ERG) and ether-à-go-go like (ELK). The human ether-à-go-go related gene (hERG) K(+) channel has been of significant interest because loss of function in the hERG channel is associated with a markedly increased risk of cardiac arrhythmias. The hERG channel has unusual kinetics with slow activation and deactivation but very rapid and voltage-dependent inactivation. The outer pore region of the hERG K(+) channel is predicted to be different from that of other members of the voltage-gated K(+) channel family. HERG has a much longer linker between the fifth transmembrane domain (SS) and the pore helix (S5P linker) compared to other families of voltage-gated K(+) channels (43 amino acids compared to 14-23 amino acids). Further, the S5P linker contains an amphipathic alpha-helix that in hERG channels probably interacts with the mouth of the pore to modulate inactivation. The human EAG and rat ELK2 channels (hEAG and rELK2) show reduced or no inactivation in comparison to hERG channels, yet both channels are predicted to contain a similarly long S5P linker to that of hERG. In this study, we have constructed a series of chimaeric channels consisting of the S1-S6 of hERG but with the S5P alpha-helical region of either hEAG or rELK2, and one consisting of the S1-S6 of rELK2 but with the S5P alpha-helical region of hERG to investigate the role of the S5P linker in inactivation. Our studies show that charged residues on the alpha-helix of the S5P linker contribute significantly to the differences in inactivation characteristics of the EAG family channels. Further, individually mutating each of the hydrophilic residues on the S5P alpha-helix of hERG to a charged residue had significant effects on the voltage dependence of inactivation and the two residues with the greatest affect when mutated to a lysine, N588 and Q592, both lie on the same face of the S5P alpha -helix. We suggest that inactivation of hERG involves the interaction of this face of the S5P alpha-helix with a charged residue on the remainder of the outer pore domain of the channel.

Animals↗
PubMed2004

S641 contributes HERG K+ channel inactivation.

The kinetics of voltage-dependent inactivation of the rapidly activating delayed rectifier, IKr, are unique among K+ channels. The human ether-a-gogo-related gene (HERG) encodes the pore-forming subunit of IKr and shares a high degree of homology with ether-a-gogo (EAG) channels that do not inactivate. Within those segments thought to contribute to the channel pore, HERG possesses several serine residues that are not present in EAG channels. Two of these serines, S620 and S631, are known to be required for inactivation. We now show that a third serine, S641, which resides in the outer portion of the sixth transmembrane segment, is also critical for normal inactivation. As with the other serines, S641 is also involved in maintaining ion selectivity of the HERG channel and alters sensitivity to block by E4031. Larger charged or polar substitutions (S641D and S641T) disrupted C-type inactivation in HERG. Smaller aliphatic and more conservative substitutions (S641A and S641C) facilitated C-type inactivation. Our data show that, like S620 and S631, S641 is another key residue for the rapid inactivation. The altered inactivation of mutations at S620, S631, and S641 were dominant, suggesting that a network of hydroxyl side chains is required for the unique inactivation, permeation, and rectification of HERG channels.

Amino Acid Sequence↗
PubMed2005

Dynamic control of hERG/I(Kr) by PKA-mediated interactions with 14-3-3.

IKs has been considered the potassium current most responsible for adrenergic/cAMP-mediated changes in cardiac repolarization during stress. Increasing biochemical, electrophysiological and genetic evidence however, points to a role for hERG/IKr in beta-adrenergic responses. Elevations of cAMP as seen in beta-adrenergic stimulation can result in PKA-dependent phosphorylation of hERG and direct binding of cAMP to the channel protein. Generally, there is a suppression of current density due to the channel phosphorylation. We recently identified a novel protein-protein interaction between hERG and the adaptor protein 14-3-3epsilon. Interaction sites exist on both N- and C-termini of hERG and the interaction is dynamic, requiring phosphorylation of the channel by PKA. When both sites bind to 14-3-3 proteins there is an acceleration and augmentation of current activation in contrast to the depression of current with phosphorylation alone. When sufficient 14-3-3 is available the phosphorylation state of the channel is stabilized and prolonged. Thus, 14-3-3 interactions with hERG provide a unique mechanism for plasticity in the autonomic control of stress-dependent regulation of cardiac membrane excitability. Here, we summarize our findings and report on our further efforts to analyse interactions between the native channel protein and 14-3-3 in cardiac myocytes.

14-3-3 Proteins↗
PubMed1997

The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes.

1. The antipsychotic drug haloperidol can induce a marked QT prolongation and polymorphic ventricular arrhythmias. In this study, we expressed several cloned cardiac K+ channels, including the human ether-a-go-go related gene (HERG) channels, in Xenopus oocytes and tested them for their haloperidol sensitivity. 2. Haloperidol had only little effects on the delayed rectifier channels Kv1.1, Kv1.2, Kv1.5 and IsK, the A-type channel Kv1.4 and the inward rectifier channel Kir2.1 (inhibition < 6% at 3 microM haloperidol). 3. In contrast, haloperidol blocked HERG channels potently with an IC50 value of approximately 1 microM. Reduced haloperidol, the primary metabolite of haloperidol, produced a block with an IC50 value of 2.6 microM. 4. Haloperidol block was use- and voltage-dependent, suggesting that it binds preferentially to either open or inactivated HERG channels. As haloperidol increased the degree and rate of HERG inactivation, binding to inactivated HERG channels is suggested. 5. The channel mutant HERG S631A has been shown to exhibit greatly reduced C-type inactivation which occurs only at potentials greater than 0 mV. Haloperidol block of HERG S631A at 0 mV was four fold weaker than for HERG wild-type channels. Haloperidol affinity for HERG S631A was increased four fold at +40 mV compared to 0 mV. 6. In summary, the data suggest that HERG channel blockade is involved in the arrhythmogenic side effects of haloperidol. The mechanism of haloperidol block involves binding to inactivated HERG channels.

Animals↗