SEARCH · PubMed Health

Results for “ERG1 Potassium Channel”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 145 records · Page 8Linked to original sources

PubMed2006

Functional significance of KCNH2 (HERG) K897T polymorphism for cardiac repolarization assessed by analysis of T-wave morphology.

BACKGROUND: Although KCNH2 (HERG) K897T polymorphism has been shown to be associated with the QT interval measured from 12-lead electrocardiogram (ECG), the functional significance of K897T polymorphism has been debated. The aim of this study was to test whether the K897T polymorphism of the KCNH2 (HERG) gene coding for the rapidly activating delayed rectifier K+ channel influences cardiac repolarization assessed by principal component analysis (PCA) of T-wave morphology. METHODS: Twelve-lead ECGs were digitized and T-wave morphology was analyzed with a PCA method in a population consisting of 228 healthy middle-aged subjects (121 women and 107 men). DNA samples were genotyped for the nucleotide 2690 A>C variation of the KCNH2 gene, corresponding to the KCNH2 K(lysine)897T(threonine) amino acid polymorphism. RESULTS: The allele frequencies were 0.86 (K) and 0.14 (T). The KCNH2 K897T polymorphism was associated with the total cosine R-to-T (TCRT), which reflects the wave front direction between depolarization and repolarization. TCRT was 0.421 in the genotype KK and 0.300 in the genotypes KT and TT (P = 0.04). The difference of TCRT was more marked between the KCNH2 K897T genotypes in women (P = 0.03) than in men (P = 0.52). CONCLUSIONS: The common K897T polymorphism of the cardiac potassium channel KCNH2 has functional significance for cardiac electrical properties. Subjects with a less common genotype, KT or TT, have smaller TCRT, which reflects dyssynchrony between depolarization and repolarization and is associated with an increased risk of cardiac mortality.

Adult↗

PubMed2000

The distinct HERG missense mutation L564P causes long QT syndrome in one French Canadian family.

BACKGROUND: Long QT syndrome is a congenital abnormality of cardiac repolarization causing syncope and sudden death from ventricular tachyarrhythmias known as torsades de pointes. This hereditary cardiac disorder often shows an increase of the value of the QT interval corrected for heart rate over 0.45 s in a 12-lead electrocardiogram. OBJECTIVE: To find and identify pertinent mutations occurring in French Canadians by extracting genomic DNA from blood samples and performing a combination of polymerase chain reaction (PCR), single-strand conformational polymorphism and DNA sequencing. RESULTS: A novel mutation was identified in the S5 region of the HERG potassium channel. In codon 564 CTA, T was replaced by C, resulting in a leucine to proline substitution. Two family members had the mutation in two distinct generations. A new restriction site was created at this position and therefore enabled the development of a rapid diagnostic test using PCR. HERG wild type and mutant potassium channel mRNAs were then expressed in Xenopus laevis oocytes. CONCLUSION: This electrophysiological study suggests that coexpression of HERG wild type and mutant L564P results in a dominant negative effect of the mutation.

Adult↗

PubMed1995

A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel.

Mutations in HERG cause an inherited cardiac arrhythmia, long QT syndrome (LQT). To define the function of HERG, we expressed the protein in Xenopus oocytes. The biophysical properties of expressed HERG are nearly identical to the rapidly activating delayed rectifier K+ current (IKr) in cardiac myocytes. HERG current is K+ selective, declines with depolarizations above 0 mV, is activated by extracellular K+, and is blocked by lanthanum. Interestingly, HERG current is not blocked by drugs that specifically block IKr in cardiac myocytes. These data indicate that HERG proteins form IKr channels, but that an additional subunit may be required for drug sensitivity. Since block of IKr is a known mechanism for drug-induced cardiac arrhythmias, the finding that HERG encodes IKr channels provides a mechanistic link between certain forms of inherited and acquired LQT.

Animals↗

PubMed2003

Molecular characterization, functional expression, and developmental profile of an ether à-go-go K+ channel in the tobacco hornworm Manduca sexta.

A very large number of evolutionarily conserved potassium channels have been identified but very little is known about their function or modulation in vivo. Metamorphosis of the tobacco hornworm, Manduca sexta, is a compelling model system for such studies because it permits analysis to be conducted at the level of identified neurons whose roles in simple behaviors and endocrine regulation are known. We present here the characterization of the first ion channel to be cloned from this animal. Partial genomic sequence for Manduca sexta ether à-go-go (Mseag) and a cDNA clone encoding the Mseag open reading frame were obtained. Genomic Southern analysis indicates that Manduca contains a single member of the eag subfamily per haploid genome. When expressed in Xenopus oocytes, MsEag channels conduct a voltage-dependent, K+ selective outward current with an inactivating component that closely resembles the Drosophila eag current. Mseag transcripts were restricted to the nervous system, adult antenna, and one set of larval skeletal muscles. Steroid hormonal regulation of Mseag expression is suggested by the temporal correlation of developmental changes in transcript expression with the changing steroid titers that promote metamorphosis. These results provide the foundation for functional and modulatory studies of the Eag family of K+ channels in Manduca, which will complement the genetic analysis in Drosophila.

Amino Acid Sequence↗

PubMed2004

Adrenergic regulation of the rapid component of the cardiac delayed rectifier potassium current, I(Kr), and the underlying hERG ion channel.

Ventricular arrhythmias are often precipitated by physical or emotional stress, in particular in patients with ischemic heart disease or hereditary long QT syndrome. Stimulation of the sympathetic nervous system in response to exercise or emotional stress causes activation of cardiac alpha- and beta-adrenoceptors. The rapid component of the delayed rectifier potassium current, I(Kr), and the underlying hERG potassium channel are critical for the regulation of heart rhythm. Recent experimental studies revealed that hERG/I(Kr) currents are modulated by alpha- and beta-adrenergic stimulation, providing a pathophysiological explanation for the increased incidence of arrhythmias during stress. This review summarizes the current knowledge on hERG/I(Kr) channel modulation by adrenergic activity. In addition, therapeutic approaches to future effective, more genotype-specific antiarrhythmic therapies are discussed.

Adrenergic alpha-Agonists↗

PubMed2003

Novel gene hKCNE4 slows the activation of the KCNQ1 channel.

The KCNE genes encode small, single transmembrane domain peptides that associate with pore-forming potassium channel subunits to form mixed complexes with unique characteristics. We have identified a novel member of the human KCNE gene family, hKCNE4. The hKCNE4 gene encodes 170 amino acid protein and is localized to chromosome 2q35-36. The protein sequence shows 90% homology to mouse KCNE4 and 38% identity to human KCNE1. Northern blot analysis revealed that hKCNE4 is expressed strongly in heart, skeletal muscle, and kidney, less in placenta, lung, and liver, and weakly in brain and blood cells. Electrophysiological study showed that hKCNE4 modulates the activation of the KCNQ1 channel.

Amino Acid Sequence↗

PubMed1996

Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides.

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.

Animals↗

PubMed1998

Long-term exposure to retinoic acid induces the expression of IRK1 channels in HERG channel-endowed neuroblastoma cells.

The modulation of inward K+ conductances was studied during neuronal differentiation of human SH-SY5Y neuroblastoma cells. Under standard culture conditions, these cells express the herg gene, and the HERG current is the main inward K+ current regulating their Vrest. After 10-20 days exposure to Retinoic Acid (RA), SH-SY5Y cells showed, in addition to HERG currents, a novel current characterized by inward rectification, dependence on the extracellular K+ concentration, and blockade by Cs+ and Ba2+, the main features of the IRK1 current. The appearance of this current is accompanied by a strong hyperpolarisation of Vrest. RT-PCR experiments confirmed that a transcript of the IRK1 (Kir 2.1) gene actually appears in SH-SY5Y cells treated for 10-20 days with RA. On the whole, data here presented demonstrate that RA-induced neuronal differentiation of neuroblastoma cells is accompanied by the switch from a HERG-driven to a IRK1-driven control of Vrest, similarly to what happens in normal differentiating neurons; however, in tumor cells, this switch does not imply the abolition of HERG channel expression.

Cation Transport Proteins↗

PubMed2006

hERG K+ channel blockade by the antipsychotic drug thioridazine: An obligatory role for the S6 helix residue F656.

The phenothiazine antipsychotic agent thioridazine has been linked with prolongation of the QT interval on the electrocardiogram, ventricular arrhythmias, and sudden death. Although thioridazine is known to inhibit cardiac hERG K(+) channels there is little mechanistic information on this action. We have investigated in detail hERG K(+) channel current (I(hERG)) blockade by thioridazine and identified a key molecular determinant of blockade. Whole-cell I(hERG) measurements were made at 37 degrees C from human embryonic kidney (HEK-293) cells expressing wild-type and mutant hERG channels. Thioridazine inhibited I(hERG) tails at -40mV following a 2s depolarization to +20mV with an IC(50) value of 80nM. Comparable levels of I(hERG) inhibition were seen with physiological command waveforms (ventricular and Purkinje fibre action potentials). Thioridazine block of I(hERG) was only weakly voltage-dependent, though the time dependence of I(hERG) inhibition indicated contingency of blockade upon channel gating. The S6 helix point mutation F656A almost completely abolished, and the Y652A mutation partially attenuated, I(hERG) inhibition by thioridazine. In summary, thioridazine is one of the most potent hERG K(+) channel blockers amongst antipsychotics, exhibiting characteristics of a preferential open/activated channel blocker and binding at a high affinity site in the hERG channel pore.

Antipsychotic Agents↗

PubMed1997

Specific block of cloned Herg channels by clofilium and its tertiary analog LY97241.

The class III antiarrhythmic drug clofilium is known to block diverse delayed rectifier K+ channels at micromolar concentrations. In the present study we investigated the potency of clofilium and its tertiary analog LY97241 to inhibit K+ channels, encoded by the human ether-a-go-go related gene (HERG). Clofilium blocked HERG channels in a voltage-dependent fashion with an IC50 of 250 nM and 150 nM at 0 and +40 mV, respectively. LY97241 was almost 10-fold more potent (IC50 of 19 nM at +40 mV). Other cloned K+ channels which are also expressed in cardiac tissue, Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv4.2, Kir2.1, or I(Ks), were not affected by 100-fold higher concentrations. Block of HERG channels by LY97241 was voltage dependent and the rate of HERG inactivation was increased by LY97241. A rise of [K+]0 decreased both, rate of HERG inactivation and LY97241 affinity. The HERG S631A and S620T mutant channels which have a strongly reduced degree of inactivation were 7-fold and 33-fold less sensitive to LY97241 blockade, indicating that LY97241 binding is affected by HERG channel inactivation. In summary, the antiarrhythmic action of clofilium and its analog LY97241 appears to be caused by their potent, but distinct ability for blocking HERG channels.

Animals↗

PubMed1997

Regulation of the human ether-a-gogo related gene (HERG) K+ channels by reactive oxygen species.

Human ether-a-gogo related gene (HERG) K+ channels are key elements in the control of cell excitability in both the cardiovascular and the central nervous systems. For this reason, the possible modulation by reactive oxygen species (ROS) of HERG and other cloned K+ channels expressed in Xenopus oocytes has been explored in the present study. Exposure of Xenopus oocytes to an extracellular solution containing FeSO4 (25-100 microM) and ascorbic acid (50-200 microM) (Fe/Asc) increased both malondialdehyde content and 2',7'-dichlorofluorescin fluorescence, two indexes of ROS production. Oocyte perfusion with Fe/Asc caused a 50% increase of the outward K+ currents carried by HERG channels, whereas inward currents were not modified. This ROS-induced increase in HERG outward K+ currents was due to a depolarizing shift of the voltage-dependence of channel inactivation, with no change in channel activation. No effect of Fe/Asc was observed on the expressed K+ currents carried by other K+ channels such as bEAG, rDRK1, and mIRK1. Fe/Asc-induced stimulation of HERG outward currents was completely prevented by perfusion of the oocytes with a ROS scavenger mixture (containing 1,000 units/ml catalase, 200 ng/ml superoxide dismutase, and 2 mM mannitol). Furthermore, the scavenger mixture also was able to reduce HERG outward currents in resting conditions by 30%, an effect mimicked by catalase alone. In conclusion, the present results seem to suggest that changes in ROS production can specifically influence K+ currents carried by the HERG channels.

Animals↗

PubMed2004

Rb+ flux through hERG channels affects the potency of channel blocking drugs: correlation with data obtained using a high-throughput Rb+ efflux assay.

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 by the Rb+ 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.

Biological Assay↗

PubMed1996

Novel missense mutation in the cyclic nucleotide-binding domain of HERG causes long QT syndrome.

Autosomal-dominant long QT syndrome (LQT) is an inherited disorder, predisposing affected individuals to sudden death from tachyarrhythmias. To identify the gene(s) responsible for LQT, we identified and characterized an LQT family consisting of 48 individuals. DNA was screened with 150 microsatellite polymorphic markers encompassing approximately 70% of the genome. We found evidence for linkage of the LQT phenotype to chromosome 7(q35-36). Marker D7S636 yielded a maximum lod score of 6.93 at a recombination fraction (theta) of 0.00. Haplotype analysis further localized the LQT gene within a 6.2-cM interval. HERG encodes a potassium channel which has been mapped to this region. Single-strand conformational polymorphism analyses demonstrated aberrant bands that were unique to all affected individuals. DNA sequencing of the aberrant bands demonstrated a G to A substitution in all affected patients; this point mutation results in the substitution of a highly conserved valine residue with a methionine (V822M) in the cyclic nucleotide-binding domain of this potassium channel. The cosegregation of this distinct mutation with LQT demonstrates that HERG is the LQT gene in this pedigree. Furthermore, the location and character of this mutation suggests that the cyclic nucleotide-binding domain of the potassium channel encoded by HERG plays an important role in normal cardiac repolarization and may decrease susceptibility to ventricular tachyarrhythmias.

Adult↗

PubMed2002

Blockade of human cardiac potassium channel human ether-a-go-go-related gene (HERG) by macrolide antibiotics.

Several macrolides have been reported to cause QT prolongation and ventricular arrhythmias such as torsades de pointes. To clarify the underlying ionic mechanisms, we examined the effects of six macrolides on the human ether-a-go-go-related gene (HERG)-encoded potassium current stably expressed in human embryonic kidney-293 cells. All six drugs showed a concentration-dependent inhibition of the current with the following IC(50) values: clarithromycin, 32.9 microM; roxithromycin, 36.5 microM; erythromycin, 72.2 microM; josamycin, 102.4 microM; erythromycylamine, 273.9 microM; and oleandomycin, 339.6 microM. A metabolite of erythromycin, des-methyl erythromycin, was also found to inhibit HERG current with an IC(50) of 147.1 microM. These findings imply that the blockade of HERG may be a common feature of macrolides and may contribute to the QT prolongation observed clinically with some of these compounds. Mechanistic studies showed that inhibition of HERG current by clarithromycin did not require activation of the channel and was both voltage- and time-dependent. The blocking time course could be described by a first-order reaction between the drug and the channel. Both binding and unbinding processes appeared to speed up as the membrane was more depolarized, indicating that the drug-channel interaction may be affected by electrostatic responses.

Anti-Bacterial Agents↗

PubMed2003

Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing.

Human hereditary long QT syndrome is a cardiac disease characterized by prolongation of the QT interval and increased susceptibility to ventricular arrhythmias and sudden cardiac death. Mutations in the human-ether-a-go-go-related gene (hERG), encoding the protein underlying the repolarizing cardiac I(Kr) potassium current, cause chromosome 7-linked long QT syndrome 2. Loss of function of mutant hERG channels may be caused by several mechanisms, including altered current kinetics, altered ion selectivity, or defective intracellular protein trafficking. Especially the latter category has become a focus of particular interest recently, because some of the mutant subunits display wild type current properties when normal trafficking is restored and channels are inserted in the cell membrane in vitro. This review summarizes the current knowledge on hERG channel trafficking under physiological and pathological conditions. In addition, therapeutic approaches to restore normal hERG trafficking in vitro and in vivo are discussed.

Animals↗

PubMed2004

Block of HERG current expressed in HEK293 cells by the Na+-channel blocker cibenzoline.

A Na(+)-channel blocker, cibenzoline, blocks the delayed rectifier potassium current ( I(k)), but its detailed action on the rapidly activating component ( I(kr)) of I(k) encoded by the human ether-a-go-go-related gene ( HERG) has not been clarified. We examined the effects of cibenzoline on stably expressed HERG current in HEK293 cells recorded by the patch-clamp technique of whole-cell configuration. Cibenzoline blocked HERG current expressed in HEK293 cells with IC(50) = 3.7 +/- 0.963 micro M and Hill coefficient = 0.74 +/- 0.12. Voltage-depended activation was shifted in a negative direction by cibenzoline. No block or minor block was induced at test depolarization of -40 to -30 mV, and the block increased with depolarization reaching a plateau at 0 mV without a further increase at positive voltages. Voltage-dependent activation of HERG currents became faster at negative test voltages but there were no changes at positive voltages after cibenzoline. No frequency-dependent block of HERG tail current by cibenzoline after equilibration was noted between 1.33 and 0.2 Hz. Steady-state inactivation of the HERG current was shifted in a negative direction by approximately 8 mV but the time constants of fast inactivation were little affected by cibenzoline. Cibenzoline blocks the I(kr)-like current reconstituted by HERG clone transfection with an IC(50) value comparable to therapeutic concentrations. Cibenzoline has a preferential affinity, at least, to the open state of the HERG channel with a rapid access to the binding site.

Action Potentials↗

PubMed2002

A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency.

The congenital long QT syndrome is a cardiac disease characterized by an increased susceptibility to ventricular arrhythmias. The clinical hallmark is a prolongation of the QT interval, which reflects a delay in repolarization caused by mutations in cardiac ion channel genes. Mutations in the HERG (human ether-à-go-go-related gene KCNH2 can cause a reduction in I(Kr), one of the currents responsible for cardiac repolarization. We describe the identification and characterization of a novel missense mutation T65P in the PAS (Per-Arnt-Sim) domain of HERG, resulting in defective trafficking of the protein to the cell membrane. Defective folding of the mutant protein could be restored by decreased cell incubation temperature and pharmacologically by cisapride and E-4031. When trafficking was restored by growing cells at 27 degrees C, the kinetics of the mutated channel resembled that of wild-type channels although the rate of activation, deactivation, and recovery from inactivation were accelerated. No positive evidence for the formation of heterotetramers was obtained by co-expression of wild-type with mutant subunits at 37 degrees C. As a consequence the clinical symptoms may be explained rather by haploinsufficiency than by dominant negative effects. This study is the first to relate a PAS domain mutation in HERG to a trafficking deficiency at body temperature, apart from effects on channel deactivation.

Adult↗

PubMed2002

Influence of amino-terminal structures on kinetic transitions between several closed and open states in human erg K+ channels.

Gating kinetics of human ether-a-go-go (eag)-related gene (HERG) K+ channel expressed in Xenopus oocytes was studied using non-inactivating channel variants carrying different structural modifications in the amino terminus. A kinetics model was elaborated to describe the behavior of full-length channels, that includes at least three open states besides the three closed states previously proposed. Deletion of the HERG-specific proximal domain (HERG D138-373) accelerated all individual forward transitions between closed states. Whereas relatively large amplitude depolarizations were required to drive full-length HERG channels to more distal open states, these were reached more easily in channels without proximal domain. Alteration of the initial eag/PAS domain by introduction of a short amino-acid sequence at the beginning of the amino terminus did not alter transitions between closed states, but prevented the channels from reaching the farthest open states that determine slower deactivation rates. This indicates that the presence of specific amino-terminal structures can be correlated with the occurrence of distinctive molecular transitions. It also demonstrates that both proximal and eag/PAS domains in the amino terminus contribute to set the gating characteristics of HERG channels.

Amino Acid Sequence↗