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Results for “Delayed Rectifier Potassium Channels”

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PubMed1983

Interaction of internal anions with potassium channels of the squid giant axon.

The interaction of internal anions with the delayed rectifier potassium channel was studied in perfused squid axons. Changing the internal potassium salt from K+ glutamate- to KF produced a reversible decline of outward K currents and a marked slowing of the activation of K channels at all voltages. Fluoride ions exert a differential effect upon K channel gating kinetics whereby activation of IK during depolarizing steps is slowed dramatically, but the rate of closing after the step is not much altered. These effects develop with a slow time course (30-60 min) and are specific for K channels over Na channels. Both the amplitude and activation rate of IK were restored within seconds upon return to internal glutamate solutions. The fluoride effect is independent of the external K+ concentration and test membrane potential, and does not recover with repetitive application of depolarizing voltage steps. Of 11 different anions tested, all inorganic species induced similar decreases and slowing of IK, while K currents were maintained during extended perfusion with several organic anions. Anions do not alter the reversal potential or shape of the instantaneous current-voltage relation of open K channels. The effect of prolonged exposure to internal fluoride could be partially reversed by the addition of cationic K channel blocking agents such as TEA+, 4-AP+, and Cs+. The competitive antagonism between inorganic anions and internal cationic K channel blockers suggests that they may interact at a related site(s). These results indicate that inorganic anions modify part of the K channel gating mechanism (activation) at a locus near the inner channel surface.

Action Potentials↗

PubMed2006

Isolated perfused and paced guinea pig heart to test for drug-induced changes of the QT interval.

INTRODUCTION: One of the biomarkers for assessing the risk of a cardiac adverse event is drug-induced prolongation of the QT interval. A model is needed for evaluating the potential liability of test compounds on QT interval in vitro. Since QT intervals can be generated from paced or spontaneously beating hearts, data so generated can also be used for validating QT(c) correction equations. METHODS: Isolated guinea pig hearts were perfused in Locke's solution according to the Langendorff method. QT intervals were routinely measured from Lead II ECG waveforms. RESULTS: Compounds known to inhibit HERG channel, such as dofetilide, prolonged the QT interval in this model. (+/-)Bay K8644, a calcium channel activator, prolonged the QT interval, while verapamil, a calcium channel blocker, shortened it. Procainamide, a sodium channel blocker, also prolonged the QT interval. Many of the compounds, which prolonged the QT interval, also prolonged PR interval, suggesting dual inhibition of the Ikr channel, the rapid component of delayed rectifier potassium channel, and the calcium channel. The QT/RR intervals exhibited a curvilinear relationship, which could be corrected into nearly straight horizontal lines by using correction equations derived from linear, parabolic, and hyperbolic models. However, these correction equations yielded different results on the QT prolongation produced by sotalol, which also slowed down the heart rate. With the data set obtained in this investigation, correction equations derived from linear and parabolic models worked better than the equations derived from the hyperbolic model. The exponential model did not fit at all. CONCLUSION: QT intervals obtained under paced conditions provide the most direct and reliable QT information for a drug. The isolated perfused and paced guinea pig heart is a convenient model for studying the effect of compounds on QT interval in vitro.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed2006

1H-NMR signal assignments and secondary structure analysis of martentoxin.

Martentoxin is a peptide of 37 amino acid residues purified from the venom of the Chinese scorpion Buthus martensi Karch, which has been demonstrated to be an inhibitor of voltage-dependent sodium channel and voltage-dependent delayed rectifier potassium channel. To elucidate the molecular mechanism of this interaction, the structure of martentoxin was studied by 2D-NMR. The secondary structure of martentoxin consists of a triple-stranded beta-sheet connected to a alpha-helical structure. This helix encompasses 10 residues from Ser11 to Lys20. The three strands of beta-sheet probably comprise residues Gly2-Asp5, Q27-N30 and Glu33-Cys36, Cys30-Asn33 with a type I'beta turn centered on Asn31-Asn32. The results indicate that martentoxin possesses the conserved beta alpha beta beta structure of all the potassium channel toxins.

Amino Acid Sequence↗

PubMed1981

Chiriquitoxin, a new tool for mapping ionic channels.

Chiriquitoxin is a new natural analog of tetrodotoxin in which the -CH2OH group on C6 has been replaced with a yet unidentified group consisting of 104 mass units. It is unique in being the only known stable analog to be equally potent as tetrodotoxin in blocking the sodium channel. It additionally interferes with the delayed rectifier (potassium) channel. In frog skeletal muscle, it significantly reduced the outward current while abolishing the inward current. It also slows the fast repolarization of the action potential and obliterates the voltage response characteristic of delayed rectification to large outward currents. It completes the tetrodotoxin for the same membrane binding site, thereby suggesting that the same molecule interferes with both the sodium and the potassium channels. A new working hypothesis is proposed in which tetrodotoxin and chiriquitoxin are postulated to bind to a membrane receptor located in the outside surface of the muscle fiber membrane. From the structure of tetrodotoxin and a presumed structure of chiriquitoxin, the Na+ and K+ channels have been estimated to be separated from each other by not less than 5 A nor much more than 15 A.

Amphibian Venoms↗

PubMed1991

Phosphorylation of K+ channels in the squid giant axon. A mechanistic analysis.

Protein phosphorylation is an important mechanism in the modulation of voltage-dependent ionic channels. In squid giant axons, the potassium delayed rectifier channel is modulated by an ATP-mediated phosphorylation mechanism, producing important changes in amplitude and kinetics of the outward current. The characteristics and biophysical basis for the phosphorylation effects have been extensively studied in this preparation using macroscopic, single-channel and gating current experiments. Phosphorylation produces a shift in the voltage dependence of all voltage-dependent parameters including open probability, slow inactivation, first latency, and gating charge transferred. The locus of the effect seems to be located in a fast 20 pS channel, with characteristics of delayed rectifier, but at least another channel is phosphorylated under our experimental conditions. These results are interpreted quantitatively with a mechanistic model that explains all the data. In this model the shift in voltage dependence is produced by electrostatic interactions between the transferred phosphate and the voltage sensor of the channel.

Animals↗

PubMed2006

Mallotoxin is a novel human ether-a-go-go-related gene (hERG) potassium channel activator.

Human ether-a-go-go-related gene (hERG) encodes a rapidly activating delayed rectifier potassium channel that plays important roles in cardiac action potential repolarization. Although many drugs and compounds block hERG channels, activators of the channel have only recently been described. Three structurally diverse synthetic compounds have been reported to activate hERG channels by altering deactivation or inactivation or by unidentified mechanisms. Here, we describe a novel, naturally occurring hERG channel activator, mallotoxin (MTX). The effects of MTX on hERG channels were investigated using the patch-clamp technique. MTX increased both step and tail hERG currents with EC(50) values of 0.34 and 0.52 microM, respectively. MTX leftward shifted the voltage dependence of hERG channel activation to less depolarized voltages ( approximately 24 mV at 2.5 microM). In addition, MTX increased hERG deactivation time constants. MTX did not change the half-maximal inactivation voltage of the hERG channel, but it reduced the slope of the voltage-dependent inactivation curve. All of these factors contribute to the enhanced activity of hERG channels. During a voltage-clamp protocol using prerecorded cardiac action potentials, 2.5 microM MTX increased the total potassium ions passed through hERG channels by approximately 5-fold. In conclusion, MTX activates hERG channels through distinct mechanisms and with significantly higher potency than previously reported hERG channel activators.

Acetophenones↗

PubMed1992

Modification of potassium channel kinetics by amino group reagents.

We have examined the actions of several amino group reagents on delayed rectifier potassium channels in squid giant axons. Three general classes of reagents were used: (1) those that preserved the positive charge of amino groups; (2) those that neutralize the charge; and (3) those that replace the positive with a negative charge. All three types of reagents produced qualitatively similar effects on K channel properties. Trinitrobenzene sulfonic acid (TNBS) neutralizes the peptide terminal amino groups and the epsilon-amino group of lysine groups. TNBS (a) slowed the kinetics of macroscopic ionic currents; (b) increased the size of ionic currents at large positive voltages; (c) shifted the voltage-dependent probability of channel opening to more positive potentials but had no effect on the voltage sensitivity; and (d) altered several properties of K channel gating currents. The actions of TNBS on gating currents suggest the presence of multiple gating current components. These effects are not all coupled, suggesting that several amino groups on the external surface of K channels are important for channel gating. A simple kinetic model that considers the channel to be composed of independent heterologous subunits is consistent with most of the modifications produced by amino group reagents.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗

PubMed1996

Effect of the class III antiarrhythmic agent E-4031 on the ATP-sensitive potassium channel in rabbit ventricular myocytes.

The class III antiarrhythmic drug E-4031, a known blocker of the delayed rectifier potassium channel (IK), might also be capable of blocking the ATP-sensitive potassium channel (IKATP). We examined this possibility by studying the effect of E-4031 on single IKATP channels in membrane patches excised from ventricular myocytes that were obtained by standard enzymatic dissociation techniques from New Zealand white rabbits. In inside-out patches, E-4031 caused a dose-dependent block of IKATP with an EC50 of 31 +/- 1 microM, Hill coefficient of 0.89 +/- 0.24 and no effect on channel conductance. Open dwell-time kinetics were fitted by two exponential components, with E-4031 causing reduction of the longer time constant. In outside-out patches, the concentration of E-4031 required to produce blockade was much higher. We conclude that E-4031 blocks the ATP-sensitive potassium channel and that it does so from within the cytoplasm, with one-to-one channel binding stoichiometry. Single channel conductance is unchanged, but the longer time constant for the open state is reduced, which suggests that E-4031 may be an open channel blocker of intermediate to slow time course.

Adenosine Triphosphate↗

PubMed1996

An essential binding surface for ShK toxin interaction with rat brain potassium channels.

An "Ala scan" analysis of ShK toxin, a 35-residue basic peptide possessing three disulfide bonds, identifies seven side chains which influence binding to brain delayed rectifier potassium channels. Additional analogs were synthesized and tested to further decipher the roles of these residues, particularly Tyr23. The inhibitory effects of these analogs on 125I-labeled dendrotoxin binding to rat brain membranes showed that replacement of Tyr23 with Ala drastically lowered the affinity of the toxin for the Kv1.2 channels. Ala substitution of Phe27 reduced potency more than 15-fold. Monosubstituted Ala analogs for Ile7, Ser20, or Lys30 each displayed 5-fold reductions in potency. Thus, aromaticity at position 23 is important for effective delayed rectifier brain K channel binding. In contrast, the aromatic residue at position 27 was not critical, since cyclohexylalanine substitution increased affinity. The solution structure of ShK toxin clusters Ile7, Arg11, Ser20, Lys22, Tyr23, and Phe27 in close proximity, forming the potassium channel binding surface of the toxin. We propose an essential binding surface on the toxin in which Lys22 and Tyr23 are major contributors, through ionic and aromatic (hydrophobic) interactions, with the potassium channel.

Amino Acid Sequence↗

PubMed1996

Identification of a Ser857-Asn857 substitution in DRK1 (KCNB1), population frequencies and lack of association to the low voltage alpha EEG trait.

A nonconservative amino acid substitution (Ser857Asn) in the human delayed-rectifier potassium channel DRK1 (KCNB1 locus), a candidate gene for the low voltage alpha electroencephalogram (EEG) trait locus (LVEEG1) at 20q13.2, and its frequency in ethnic population samples are described. The frequency of Asn857 in seven different ethnic population samples, totalling more than 1600 individuals, ranged from zero to greater than 3%. However, no association was found between Asn857 and the low voltage alpha EEG trait (LVA) in a population of 105 subjects assessed for the EEG, 24 of whom actually had LVA.

Alleles↗

PubMed1996

Evidence for an internal phenylalkylamine action on the voltage-gated potassium channel Kv1.3.

We characterized the action of verapamil and N-methyl-verapamil on current through the delayed-rectifier potassium channel Kv1.3 mouse (mKv1.3). The whole-cell and inside-out configuration of the patch-clamp technique was used to examine the channel properties after injection of in vitro transcribed cRNA into rat basophilic leukemia cells. The action of verapamil on current through mKv1.3 channels could be separated into an acceleration of the rate of current decay during depolarizing pulses and a reduction of steady state peak current when applied either extracellularly or intracellularly. Both effects were greatly reduced when the membrane-impermeable N-methyl-verapamil was applied extracellularly, but it affected current through mKv1.3 channels similar to verapamil if applied to the intracellular side of the membrane. Mutations in the outer vestibule of the mKv1.3 channel did not change the ability of verapamil to accelerate the mKv1.3 current decay during depolarizing pulses, whereas the reduction of the steady state peak current by verapamil applied either extracellularly and intracellularly and by N-methyl-verapamil applied intracellularly was decreased approximately 25-fold in all three cases. Substances known to interact with an extracellular site of the channel (e.g., extracellularly applied tetraethylammonium or kaliotoxin) did not compete with extracellularly applied verapamil on blocking steady state peak current, whereas intracellularly applied tetraethylammonium, which is known to interact with an intracellular site of the channel, was able to reduce the effect of extracellularly applied verapamil on blocking steady state peak current, suggesting competition for a common binding site between verapamil and intracellularly applied tetraethylammonium. The results from the competition experiments as well as from the mutations in the outer vestibule of mKv1.3 are compatible with the idea that verapamil applied extracellularly moves through the membrane to reach its internal binding site on the mKv1.3 channel.

Amino Acid Sequence↗

PubMed1994

[Studies on glycine receptor, acetylcholine receptor and ion channels expressed in amphibian oocytes after injection of chicken retina mRNA].

Glycine receptor, acetylcholine receptor and voltage dependent ion channels expressed in amphibian oocytes after injection of chicken retinal mRNA were studied by using voltage clamp technique. The current response to glycine was proved as small, and the acetylcholine receptor was identified as N type. Aspartate, serotonin and dopamine induced no responses. In addition, voltage dependent ion channels were detected, and were identified as delayed rectifier potassium channel and sodium channel.

Animals↗

PubMed1999

Identification and biochemical characterization of a novel nortriterpene inhibitor of the human lymphocyte voltage-gated potassium channel, Kv1.3.

A novel nortriterpene, termed correolide, purified from the tree Spachea correae, inhibits Kv1.3, a Shaker-type delayed rectifier potassium channel present in human T lymphocytes. Correolide inhibits 86Rb+ efflux through Kv1.3 channels expressed in CHO cells (IC50 86 nM; Hill coefficient 1) and displays a defined structure-activity relationship. Potency in this assay increases with preincubation time and with time after channel opening. Correolide displays marked selectivity against numerous receptors and voltage- and ligand-gated ion channels. Although correolide is most potent as a Kv1.3 inhibitor, it blocks all other members of the Kv1 family with 4-14-fold lower potency. C20-29-[3H]dihydrocorreolide (diTC) was prepared and shown to bind in a specific, saturable, and reversible fashion (Kd = 11 nM) to a single class of sites in membranes prepared from CHO/Kv1.3 cells. The molecular pharmacology and stoichiometry of this binding reaction suggest that one diTC site is present per Kv1.3 channel tetramer. This site is allosterically coupled to peptide and potassium binding sites in the pore of the channel. DiTC binding to human brain synaptic membranes identifies channels composed of other Kv1 family members. Correolide depolarizes human T cells to the same extent as peptidyl inhibitors of Kv1.3, suggesting that it is a candidate for development as an immunosuppressant. Correolide is the first potent, small molecule inhibitor of Kv1 series channels to be identified from a natural product source and will be useful as a probe for studying potassium channel structure and the physiological role of such channels in target tissues of interest.

Animals↗

PubMed1998

The biological activity of selected cyclic dipeptides.

Cyclic dipeptides are widely used as models for larger peptides because of their simplicity and limited conformational freedom. Some cyclic dipeptides have been shown to be antiviral, antibiotic and anti-tumour. The aim of this study was to determine the biological activity of four cyclic dipeptides synthesized in this laboratory: cyclo(L-phenylalanyl-L-prolyl), cyclo(L-tyrosyl-L-prolyl), cyclo(L-tryptophanyl-L-prolyl) and cyclo(L-tryptophanyl-L-tryptophanyl). The enhancement or inhibition of calcium channels in ventricular myocytes from rats and delayed-rectifier potassium channels in ventricular myocytes from guinea-pigs were determined by use of the whole-cell patch-clamp technique. The induction of differentiation in HT-29 cells was assessed by assaying for an increase in the expression of alkaline phosphatase. Antibiotic properties against Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Staphylococcus aureus, Bacillus subtilus and Streptococcus sp. were determined by use of the Kirby-Bauer disc-diffusion assay. Results from these assays indicate that the cyclic dipeptides have biological activity in both prokaryotes and eukaryotes. Three of the dipeptides block cation channels in ventricular myocytes and all increase the expression of alkaline phosphatase. All the dipeptides have concentration-dependent antibacterial properties. These results suggest that with increased solubility the cyclic dipeptides might have potential as muscle relaxants, anti-tumour compounds and antibiotics.

Anti-Bacterial Agents↗

PubMed2002

Role of glycosylation in cell surface expression and stability of HERG potassium channels.

The human ether-à-go-go-related gene (HERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel in the heart. We previously showed that HERG channel protein is modified by N-linked glycosylation. HERG protein sequence contains two extracellular consensus sites for N-linked glycosylation (N598, N629). In this study, we used the approaches of site-directed mutagenesis and biochemical modification to inhibit N-linked glycosylation and studied the role of glycosylation in the cell surface expression and turnover of HERG channels. Our results show that N598 is the only site for N-linked glycosylation and that glycosylation is not required for the cell surface expression of functional HERG channels. In contrast, N629 is not used for glycosylation, but mutation of this site (N629Q) causes a protein trafficking defect, which results in its intracellular retention. Pulse-chase experiments show that the turnover rate of nonglycosylated HERG channel is faster than that of the glycosylated form, suggesting that N-linked glycosylation plays an important role in HERG channel stability.

Amino Acid Sequence↗

PubMed2006

The single nucleotide polymorphisms of I(Ks) potassium channel genes and their association with atrial fibrillation in a Chinese population.

Recent studies suggest that genetic mutation of the slow delayed rectifier potassium channel (I(Ks)) may underlie atrial fibrillation (AF). We investigated the association between AF and the single nucleotide polymorphisms (SNPs) of genes KCNQ1, KCNE1 and KCNE4 associated with this channel. Common non-synonymous SNPs in KCNQ1 and KCNE1 known to be frequent in Asian people were selected and direct sequencing of KCNE4 was performed to identify possible SNPs. The AF group consisted of 142 hospitalized patients with AF, the community control group consisted of 120 subjects, and a ward control group consisted of 118 hospitalized patients without AF. Restriction fragment length polymorphism analysis was performed to determine the genotypes. The minor allele frequencies of P448R, R519H, G643S for KCNQ1 and G38S and D85N for KCNE1 in the AF group, the community control group and the ward control group were 9.9, 7.9, 9.3%; 0, 0, -; 4.3, 4.2, 1.7%; 28.4, 31.7, 29.7%; 0.7, 0.4%, -, respectively. There was no significant association between these SNPs and AF phenotype. There were eight SNPs in the whole length of KCNE4 plus 1,000 bases upstream of this gene including the non-synonymous SNP E145D. Logistical regression analysis revealed a difference in the distribution of KCNE4 E145D in the AF and the community control group (minor allele frequency was 34.0 versus 27.1% respectively, OR = 1.66, p = 0.044). We provided the frequencies of non-synonymous SNPs of KCNQ1 and KCNE1 in Chinese population; none of these SNPs was associated with AF. But KCNE4 E145D may be associated with the AF phenotype.

Aged↗

PubMed1996

Effects of potassium channel blockers on the action potentials and contractility of the rat right ventricle.

1. The effects of several potassium channel blockers on the action potentials and contractile force of the electrically driven rat right ventricle have been determined. 2. Glibenclamide, which blocks the ATP-sensitive potassium channels, had no effect on the ventricular action potentials or contractile force responses. 3. 4-Aminopyridine, which blocks the Na(+)-activated potassium channels in ventricles, at 0.3-3 mM increased the amplitude and prolonged the action potentials, and also augmented the force responses to cardiac stimulation and to isoprenaline. 4. Clofilium, a selective blocker of the delayed outward rectifying potassium channel, at 0.1 and 0.3 microM prolonged the action potentials. At 0.1 microM, clofilium augmented the cardiac stimulation responses and, at 0.3 microM, clofilium augmented the maximal responses to isoprenaline. At 1 and 3 microM, clofilium had a lesser ability to prolong action potentials and did not alter force responses. 5. Procaine blocks the Na(+)-activated and the delayed outward rectifying potassium channels and, at higher concentrations, sodium channels. Procaine, at 30 microM, prolonged the action potentials and augmented the force responses to isoprenaline, presumably by blocking potassium channels. Procaine, at 1 mM, had no effect on action potentials but reduced the maximal force responses to isoprenaline, probably by blocking sodium channels. 6. Tetraethylammonium blocks the inward rectifying and delayed outward rectifying potassium channels. Tetraethylammonium, at 1 and 3 mM, prolonged the action potentials and augmented all of the force responses; these effects are likely to be predominantly due to blocking the outward rectifying potassium channel. Thus, in the presence of procaine, the effects of tetraethylammonium are predominantly due to the additional blockade of the inward rectifying potassium channel and there were no effects. 7. None of the potassium channel blockers at any of the concentrations tested had arrhythmogenic effects alone or in the presence of isoprenaline. 8. In summary, this study has shown that blockade of the Na(+)-activated and the delayed outward rectifying, but not the ATP-sensitive or inward rectifying, potassium channel is associated with prolongation of the action potentials, augments the contractile force responses, and is not arrhythmogenic on the rat right ventricle. New drugs that block the Na(+)-activated or delayed outward rectifying potassium channel may have potential as positive inotropes in the treatment of heart failure.

4-Aminopyridine↗

PubMedDate not supplied

A mechanism for the potential proarrhythmic effect of acidosis, bradycardia, and hypokalemia on the blockade of human ether-a-go-go-related gene (HERG) channels.

Many drugs are proarrhythmic by inhibiting the cardiac rapid delayed rectifier potassium channel (IKr). In this study, we use quinidine as an example of highly proarrhythmic agent to investigate the risk factors that may facilitate the proarrhythmic effects of drugs. We studied the influence of pacing, extracellular potassium, and pH on quinidine's IKr blocking effect, all potential factors influencing quinidine's cardiac toxicity. Since the HERG gene encodes IKr, we studied quinidine's effect on HERG expressed in Xenopus oocytes by the 2-electrode voltage clamp technique. When extracellular K+ was 5 mmol/L, quinidine blocked the HERG current dose dependently, with an IC50 of 6.3 +/- 0.2 micromol/L. The blockade was much more prominent at more positive membrane potentials. The inhibition of HERG by quinidine was not use dependent. There was no significant difference between block with or without pacing. When extracellular K+ was lowered to 2.5 mmol/L, the current inhibition by quinidine was enhanced, and IC50 decreased to 4.6 +/- 0.5 micromol/L. At 10 mmol/L extracellular K+, there was less inhibition by quinidine and the IC50 was 11.2 +/- 3.1 micromol/L. Extracellular acidification decreased both steady state and tail currents of HERG. We conclude that the inhibitory effect of quinidine on IKr was decreased with extracellular acidification, which may produce heterogeneity in the repolarization between normal and ischemic cardiac tissue. Thus, the use-independent blockade of IKr by QT-prolonging agents such as quinidine may contribute to cardiac toxicity with bradycardia, hypokalemia, and acidosis further exaggerating the proarrhythmic potential of these agents.

Acidosis↗