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Results for “Delayed Rectifier Potassium Channels”

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PubMed2006

The action of the novel gastrointestinal prokinetic prucalopride on the HERG K+ channel and the common T897 polymorph.

The human ether-à-go-go related gene (HERG) encodes the alpha-subunit of a delayed rectifier potassium channel important in the repolarisation of the cardiac action potential. Excessive action potential prolongation through HERG channel inhibition is associated with a risk of torsade de pointes arrhythmias and is a major challenge for drug development. The acute effects of the novel prokinetic prucalopride were examined on heterologously expressed HERG channels in human embryonic kidney (HEK) 293 cells using the whole-cell patch-clamp technique. Prucalopride inhibited HERG channels in a concentration-dependent manner with an IC(50) of 4.1 microM. Prucalopride significantly slowed channel deactivation and recovery from inactivation, accelerated and altered the extent of inactivation. Similar concentration-dependency and kinetic changes were observed with the minor T897 polymorphic HERG variant. Prucalopride block was frequency-independent due to rapid state-dependent block, with binding occurring in the open and inactivated states. Though prucalopride blocks HERG channels this is unlikely to be significant at clinically relevant concentrations.

Benzofurans↗

PubMed1996

Multiple mechanisms in the long-QT syndrome. Current knowledge, gaps, and future directions. The SADS Foundation Task Force on LQTS.

The congenital long-QT syndrome (LQTS) is characterized by prolonged QT intervals, QT interval lability, and polymorphic ventricular tachycardia. The manifestations of the disease vary, with a high incidence of sudden death in some affected families but not in others. Mutations causing LQTS have been identified in three genes, each encoding a cardiac ion channel. In families linked to chromosome 3, mutations in SCN5A, the gene encoding the human cardiac sodium channel, cause the disease, Mutations in the human ether-à-go-go-related gene (HERG), which encodes a delayed-rectifier potassium channel, cause the disease in families linked to chromosome 7. Among affected individuals in families linked to chromosome 11, mutations have been identified in KVLQT1, a newly cloned gene that appears to encode a potassium channel. The SCN5A mutations result in defective sodium channel inactivation, whereas HERG mutations result in decreased outward potassium current. Either mutation would decrease net outward current during repolarization and would thereby account for prolonged QT intervals on the surface ECG. Preliminary data suggest that the clinical presentation in LQTS may be determined in part by the gene affected and possibly even by the specific mutation. The identification of disease genes in LQTS not only represents a major milestone in understanding the mechanisms underlying this disease but also presents new opportunities for combined research at the molecular, cellular, and clinical levels to understand issues such as adrenergic regulation of cardiac electrophysiology and mechanisms of susceptibility to arrhythmias in LQTS and other settings.

Cardiology↗

PubMed2005

Biochemical characterization of the native Kv2.1 potassium channel.

Functional diversity of potassium channels in both prokaryotic and eukaryotic cells suggests multiple levels of regulation. Posttranslational regulation includes differential subunit assembly of homologous pore-forming subunits. In addition, a variety of modulatory subunits may interact with the pore complex either statically or dynamically. Kv2.1 is a delayed rectifier potassium channel isolated by expression cloning. The native polypeptide has not been purified, hence composition of the Kv2.1 channel complexes was not well understood. Here we report a biochemical characterization of Kv2.1 channel complexes from both recombinant cell lines and native rat brain. The channel complexes behave as large macromolecular complexes with an apparent oligomeric size of 650 kDa as judged by gel filtration chromatography. The molecular complexes have distinct biochemical populations detectable by a panel of antibodies. This is indicative of functional heterogeneity. Despite mRNA distribution in a variety of tissues, the native Kv2.1 polypeptides are more abundantly found in brain and have predominantly Kv2.1 subunits but not homologous Kv2.2 subunits. The proteins precipitated by anti-Kv2.1 and their physiological relevance are of interest for further investigation.

Amino Acid Sequence↗

PubMed2006

Isolation and characterization of Jingzhaotoxin-V, a novel neurotoxin from the venom of the spider Chilobrachys jingzhao.

Jingzhaotoxin-V (JZTX-V), a 29-residue polypeptide, is derived from the venom of the spider Chilobrachys jingzhao. Its cDNA determined by rapid amplification of 3' and 5'-cDNA ends encoded an 83-residue precursor with a pro-region of 16 residues. JZTX-V inhibits tetrodotoxin-resistant and tetrodotoxin-sensitive sodium currents in rat dorsal root ganglion neurons with IC50 values of 27.6 and 30.2 nM, respectively. Moreover, the toxin exhibits high affinity to the resting closed states of the channels. JZTX-V also inhibits Kv4.2 potassium currents expressed in Xenpus Laevis oocytes (IC50=604.2 nM), but has no effects on outward delay-rectified potassium channels expressed in Xenopus laevis oocytes. JZTX-V alters the gating properties of sodium channels by shifting the activation curves to the depolarizing direction and the inactivation curves to the hyperpolarizing direction. Small unilamellar vesicles binding assays show that the partitioning of JZTX-V into lipid bilayer requires negatively charged phospholipids. The phospholipid membrane binding activity of JZTX-V is also verified using intrinsic tryptophan fluorescence analysis as well as acrylamide-quenching assays. Importantly, human multiple sodium channel subtypes are attractive targets for treatment of pain, highlighting the importance of JZTX-V as potential lead for drug development.

Acrylamide↗

PubMed2003

[A novel KCNQ1 mutation in Chinese with congenital long QT syndrome].

OBJECTIVE: Congenital long QT syndrome (LQTS) is an inherited disorder of cardiac repolarization characterized by prolongation of QT interval and polymorphic ventricular tachycardia torsade de pointes (TdP) in the electrocardiogram (ECG). Clinical symptoms include recurrent syncope, seizure or even sudden death. It is caused by mutations of at least seven genes, six of them encoding ion channels that determine the duration of ventricular action potentials. One of these genes, KCNQ1, encodes an alpha-subunit of cardiac slowly activated delayed rectifier potassium channel. Patients carrying mutations of KCNQ1 are named as LQT1, which accounts for 42% of patients with LQTS. This study sought to analyze the clinical data of Chinese with LQTS and to screen for the mutations of KCNQ1. METHODS: The universally accepted phenotypic criteria of LQTS was used for identification of probands. There were six families with LQTS. They were enrolled in this study. Clinical and ECG data of each family member were recorded. Genomic DNA was prepared from peripheral blood lymphocytes. Polymerase chain reaction-single strand conformation polymorphism analysis was used to screen for mutations throughout the whole coding region of KCNQ1 and DNA sequencing was performed to determine the exact mutation site. RESULTS: There were totally 13 patients in the six LQTS families. Five were male and eight female. One suffered from sudden death, 10 had syncope and 2 were asymptomatic. Eleven of the 13 patients had ECG data. Their QT and QTc (mean +/- SD) were (0.460 +/- 0.058) s and (0.516 +/- 0.058) s, respectively. TdP was observed in 3 patients (27%) during the syncope attack. By PCR-SSCP analysis, two novel KCNQ1 deletion mutations 356-357 Delta QQ and 626-631 Delta GSGGPP were identified in 7 patients of 2 families. None of 50 normal individuals carried these mutations, indicating these two mutations were likely to cause the disease. In addition, P448R was found in one affected and some unaffected members in other two families and in 7 of 50 (14%) normal individuals, indicating that this might be a polymorphism. All the three mutations located in C-terminal domain of KCNQ1 protein. CONCLUSIONS: Two novel deletion mutations and one novel polymorphism of KCNQ1 gene were identified among 6 Chinese families with LQTS.

Adolescent↗

PubMed2000

Inhibition of HERG potassium channels by the antimalarial agent halofantrine.

Halofantrine is a widely used antimalarial agent which has been associated with prolongation of the 'QT interval' of the electrocardiogram (ECG), torsades de pointes and sudden death. Whilst QT prolongation is consistent with halofantrine-induced increases in cardiac ventricular action potential duration, the cellular mechanism for these observations has not been previously reported. The delayed rectifier potassium channel, I(Kr), is a primary site of action of drugs causing QT prolongation and is encoded by the human-ether-a-go-go-related gene (HERG). We examined the effects of halofantrine on HERG potassium channels stably expressed in Chinese hamster ovary (CHO-K1) cells. Halofantrine blocked HERG tail currents elicited on repolarization to -60 mV from +30 mV with an IC(50) of 196.9 nM. The therapeutic plasma concentration range for halofantrine is 1.67-2.98 microM. Channel inhibition by halofantrine exhibited time-, voltage- and use-dependence. Halofantrine did not alter the time course of channel activation or deactivation, but inactivation was accelerated and there was a 20 mV hyperpolarizing shift in the mid-activation potential of steady-state inactivation. Block was enhanced by pulses that render channels inactivated, and channel blockade increased with increasing duration of depolarizing pulses. We conclude that HERG channel inhibition by halofantrine is the likely underlying cellular mechanism for QT prolongation. Our data suggest preferential binding of halofantrine to the open and inactivated channel states.

Animals↗

PubMed1989

Beta-adrenergic modulation of cardiac ion channels. Differential temperature sensitivity of potassium and calcium currents.

beta-Adrenergic stimulation of ventricular heart cells results in the enhancement of two important ion currents that regulate the plateau phase of the action potential: the delayed rectifier potassium channel current (IK) and L-type calcium channel current (ICa). The temperature dependence of beta-adrenergic modulation of these two currents was examined in patch-clamped guinea pig ventricular myocytes at various steps in the beta-receptor/cyclic AMP-dependent protein kinase pathway. External applications of isoproterenol and forskolin were used to activate the beta-receptor and the enzyme adenylate cyclase, respectively. Internal dialysis of cyclic 3',5'-adenosine monophosphate (cAMP) or the catalytic subunit of cAMP-dependent protein kinase (CS), as well as the external addition of 8-chlorphenylthio cAMP (CPT-cAMP) was applied to increase intracellular levels of cAMP and CS. Isoproterenol-mediated increases in IK, but not ICa, were found to be very temperature dependent over the range of 20-37 degrees C. At room temperature (20-22 degrees C) isoproterenol produced a large (threefold) enhancement of ICa but had no effect on IK. In contrast, at warmer temperatures (30-37 degrees C) both currents increased in the presence of this agonist and the kinetics of IK were slowed at -30 mV. A similar temperature sensitivity also existed after exposure to forskolin, CPT-cAMP, cAMP, and CS, suggesting that this temperature sensitivity of IK may arise at the channel protein level. Modulation of IK during each of these interventions was accompanied by a slowing in IK kinetics. Thus, regulation of cardiac potassium channels but not calcium channels involves a temperature-dependent step that occurs after activation of the catalytic subunit of cAMP-dependent protein kinase.

Adenylyl Cyclases↗

PubMed2002

Anomalous effects of external TEA on permeation and gating of the A-type potassium current in H. aspersa neuronal somata.

The model proposed for external TEA block of Shaker K+ channels predicts a proportional relationship between TEA sensitivity and calculated electrical distance derived from measurements of voltage dependence of TEA block. In the present study, we examined this relationship for the A-type K+ current (IA) of Helix aspersa in neuronal somata using the whole-cell patch-clamp technique. External TEA inhibited IA with strong voltage dependence, such that the TEA dissociation constant was increased at depolarized test potentials. The half-inhibition constant (V0.5) for TEA block was approximately 21 mM at 0 mV, and V0.5 increased to approximately 67 mM at 50 mV. The calculated electrical distance for TEA block suggested that TEA traversed 65% of the way into the membrane electrical field. TEA also caused significant shifts in the voltage-dependence of A-type K+ channel gating. For example, at TEA concentrations below that required to fully suppress delayed outward currents, TEA caused depolarizing shifts in the voltage-dependence of A-type channel activation, steady-state inactivation, time for removal of inactivation, and slowed channel activation kinetics. Taken together, these observations suggest that TEA biased the local field potential near voltage-sensing domains of A-type K+ channels, causing the transmembrane electrical field to be relatively hyperpolarized in the presence of TEA. In summary, the calculated electrical distance of TEA block of A-type K+ channels in H. aspersa neurons is unprecedented among other K+ channels. This raises concerns about the conventional interpretation of this value. Furthermore, the voltage-dependent properties of IA are modified by TEA at concentrations previously used to isolate delayed rectifier potassium channels (IKDR) selectively. This lack of specificity has important implications for recent, as well as future studies of IA in H. aspersa and possibly other snail neurons.

Animals↗

PubMed1992

Voltage-sensitive and solvent-sensitive processes in ion channel gating. Kinetic effects of hyperosmolar media on activation and deactivation of sodium channels.

Kinetic effects of osmotic stress on sodium ionic and gating currents have been studied in crayfish giant axons after removal of fast inactivation with chloramine-T. Internal perfusion with media made hyperosmolar by addition of formamide or sucrose, reduces peak sodium current (before and after removal of fast inactivation with chloramine-T), increases the half-time for activation, but has no effect on tail current deactivation rate(s). Kinetics of ON and OFF gating currents are not affected by osmotic stress. These results confirm (and extend to sodium channels) the separation of channel gating mechanisms into voltage-sensitive and solvent-sensitive processes recently proposed by Zimmerberg J., F. Bezanilla, and V. A. Parsegian. (1990. Biophys. J. 57:1049-1064) for potassium delayed rectifier channels. Additionally, the kinetic effects produced by hyperosmolar media seem qualitatively similar to the kinetic effects of heavy water substitution in crayfish axons (Alicata, D. A., M. D. Rayner, and J. G. Starkus. 1990. Biophys. J. 57:745-758). However, our observations are incompatible with models in which voltage-sensitive and solvent-sensitive gating processes are presumed to be either (a) strictly sequential or, (b) parallel and independent. We introduce a variant of the parallel model which includes explicit coupling between voltage-sensitive and solvent-sensitive processes. Simulations of this model, in which the total coupling energy is as small as 1/10th of kT, demonstrate the characteristic kinetic changes noted in our data.

Animals↗

PubMed2006

Determination of hERG channel blockers using a decision tree.

A decision tree approach for the in silico prediction of Torsade de Pointes (TdP)-causing drugs is presented. As TdP is frequently associated with QT-interval prolongation due to inhibition of the rapid activating delayed rectifier potassium channel in the heart (hERG channel), the properties of such blockers were investigated by molecular modeling and semi-empirical AM1 molecular orbital calculations. In addition, we derived a pharmacophoric SMARTS string using structural information from high affinity compounds. A corresponding search in the PubChem database identified several compounds that exhibit QT-interval prolonging activity that were not among our data set. This SMARTS string furthermore showed to be the most significant descriptor in the decision tree approach from which guidelines for the design of safe compounds are suggested.

Decision Trees↗

PubMed2004

Oscillatory activity within rat substantia gelatinosa in vitro: a role for chemical and electrical neurotransmission.

Although rhythmic behaviour of mammalian spinal ventral horn networks has been extensively studied little is known about oscillogenesis in the spinal dorsal horn. The aims of this in vitro study were to record and determine the underlying mechanisms of potassium-evoked network field oscillations in the substantia gelatinosa of the neonatal rat dorsal horn, a lamina involved in nociceptive processing. Transient pressure ejection of a potassium solution evoked reproducible rhythmic activity in discrete areas of the substantia gelatinosa which lasted for 5-15 s with a single prominent peak in the 4-12 Hz frequency band (7.7 +/- 0.1 Hz, n = 60). Oscillations of similar frequency and amplitude were also observed in isolated dorsal horn quadrants. Application of CNQX (10 microm) reduced peak power amplitude and integrated power area (from 4 to 12 Hz) of the power spectrum, whereas D-AP5 (50 microm) had no effect on the potassium-evoked rhythm. Bicuculline (30 microm) or strychnine (10 microm) reduced the power amplitude and area. On combination of bicuculline (30 microm) and strychnine (10 microm) the reductions in power amplitude and area were not significantly different (P > 0.05) when compared with application of either drug alone. The gap junction blockers carbenoxolone (100 microm) or octanol (1 mM) significantly reduced power amplitude and area. Although TTX (1 microm) or a calcium-free perfusate both caused reductions in the power amplitude and area, potassium-evoked rhythmic activity persisted. However, this persistent rhythm was further reduced on combination of calcium-free perfusate with octanol (1 mM) and was abolished using a cocktail of drugs. Blockade of the potassium delayed rectifier current by tetraethylammonium (5 mM) or the hyperpolarization-activated current (I(h)) by ZD7288 (10 microm) disrupted the synchronization of the potassium-induced oscillation. The frequency of potassium-induced rhythms was unaffected by any of the drugs tested. These novel findings demonstrate that transient pressure ejection of potassium evokes oscillatory activity in the substantia gelatinosa in vitro. This rhythm is partly dependent upon various receptors (AMPA/kainate, GABA(A) and glycine), ion channels (potassium delayed rectifier and I(h)) and gap junctions. Oscillatory behaviour in the substantia gelatinosa could potentially play a role in the processing of nociceptive signals.

Animals↗

PubMed2004

Jingzhaotoxin-I, a novel spider neurotoxin preferentially inhibiting cardiac sodium channel inactivation.

Jingzhaotoxin-I (JZTX-I), a 33-residue polypeptide, is derived from the Chinese tarantula Chilobrachys jing-zhao venom based on its ability to evidently increase the strength and the rate of vertebrate heartbeats. The toxin has three disulfide bonds with the linkage of I-IV, II-V, and III-VI that is a typical pattern found in inhibitor cystine knot molecules. Its cDNA determined by rapid amplification of 3'- and 5'-cDNA ends encoded a 62-residue precursor with a small proregion of eight residues. Whole-cell configuration indicated that JZTX-I was a novel neurotoxin preferentially inhibiting cardiac sodium channel inactivation by binding to receptor site 3. Although JZTX-I also exhibits the interaction with channel isoforms expressing in mammalian and insect sensory neurons, its affinity for tetrodotoxin-resistant subtype in mammalian cardiac myocytes (IC50 = 31.6 nm) is approximately 30-fold higher than that for tetrodotoxin-sensitive subtypes in latter tissues. Not affecting outward delay-rectified potassium channels expressed in Xenopus laevis oocytes and tetrodotoxin-resistant sodium channels in mammal sensory neurons, JZTX-I hopefully represents a potent ligand to discriminate cardiac sodium channels from neuronal tetrodotoxin-resistant isoforms. Furthermore, different from any reported spider toxins, the toxin neither modifies the current-voltage relationships nor shifts the steady-state inactivation of sodium channels. Therefore, JZTX-I defines a new subclass of spider sodium channel toxins. JZTX-I is an alpha-like toxin first reported from spider venoms. The result provides an important witness for a convergent functional evolution between spider and other animal venoms.

Amino Acid Sequence↗

PubMed1996

Modulation of Ca2+ channels, charge movement and Ca2+ transients by heparin in frog skeletal muscle fibres.

This study is an investigation into the modulatory effects of heparin, a component of the extracellular matrix that binds to dihydropyridine receptors, on contraction and Ca2+ channels in frog skeletal muscle. Using tension and Ca2+ signal measurements in single intact skeletal muscle cells we have found that heparin (100-200 micrograms ml-1) substantially potentiates twitch and tetanic tension (55% and 28%, respectively). In contrast, heparin reduces the amplitude of K+ contractures. Heparin most likely potentiates twitch tension by prolonging action potentials. The ionic basis of this effect was investigated in voltage-clamp experiments. Membrane currents were monitored in voltage-clamped segments of single fibres using the triple Vaseline gap technique. We found that heparin partially blocks delayed rectifier potassium channels. The depressive effects of heparin on K+ contractures prompted us to investigate the effects of heparin on charge movement and Ca2+ currents (ICa) under voltage-clamp. Charge movement was measured using a subtraction procedure that employed a -20 mV control pulse from a holding potential of -100 mV. Heparin depresses the total charge by 25%. We propose that the reduction in the amplitude of potassium contractures is related to a partial blockade of charge movement. Extracellular heparin shifts the ICa-V relation toward more negative voltages and delays the deactivation of tail currents. Double pulse experiments revealed that conditioning depolarizations speed the activation of ICa during test depolarizations. Heparin does not affect this process. The primary action of heparin is to accelerate the activation of ICa during pulses not preceded by conditioning depolarizations. Overall, the kinetic effects of heparin on ICa would increase the Ca2+ influx associated with action potentials. However, mechanical and optical experiments performed in Ca(2+) -free solutions and in the presence of Ca2+ channel blockers revealed that twitch and tetanic potentiation occur even in the absence of Ca(2+) -influx.

Action Potentials↗

PubMed1984

Effect of pore structure on energy barriers and applied voltage profiles. II. Unsymmetrical channels.

This paper examines "realistic" pores, i.e., ones that are neither symmetric nor of uniform diameter. Methods are described that permit estimation of the image potential for an ion in an aqueous pore spanning a lipid membrane and for the electric field produced in such a pore when a transmembrane potential is applied. They are used to model features of the delayed rectifier potassium channel. Constraints on the geometry of the exterior mouth, the dielectric properties of the narrow part of the pore and the conduction mechanism are determined for this channel.

Animals↗

PubMed1990

Solute inaccessible aqueous volume changes during opening of the potassium channel of the squid giant axon.

We have applied solutions with varying osmotic pressures symmetrically to the inside and outside of perfused, TTX-treated, giant axons. The potassium conductance G decreased with increasing osmotic stress, but there was no effect on either the shape or the position of the voltage-current curve. One must distinguish three possible actions of the osmotic agent: osmotic stress, channel blocking, and lowered solution conductivity. To do so, we compared results obtained working with pairs of internal and external solutions of either (a) equal osmotic stress, (b) equal conductivity, or (c) the same blocking agent. There was the same change in G irrespective of the type of stressing species (sorbitol or sucrose); this provides some evidence against a blocking mechanism. The conductivity of the external solution had a small effect on K currents; internal solution conductivity had none. A change in series resistance of the Schwann cell layer could account for the small effect of external solution conductivity. The primary cause of G depression appears, then, to be the applied osmotic stress. Using this result, we have developed models in which the channel has a transition between closed states under voltage control but osmotically insensitive and a closed/open step that is voltage-independent but osmotically sensitive. We have assumed that the conductance of this open state does not change with osmotic stress. In this way, we estimate that an additional 1,350 +/- 200 A3 or 40-50 molecules of solute-inaccessible water appear to associate with the average delayed rectifier potassium channel of the squid axon when it opens.

Animals↗

PubMed1998

Evidence for a new class of scorpion toxins active against K+ channels.

cDNAs encoding novel long-chain scorpion toxins (64 amino acid residues, including only six cysteines) were isolated from cDNA libraries produced from the venom glands of the scorpions Androctonus australis from Old World and Tityus serrulatus from New World. The encoded peptides were very similar to a recently identified toxin from T. serrulatus, which is active against the voltage-sensitive 'delayed-rectifier' potassium channel, but they were completely different from the long-chain and short-chain scorpion toxins already characterised. However, there was some sequence similarity (42%) between these new toxins, Aa TX Kbeta and Ts TX Kbeta, and scorpion defensins purified from the hemolymph of Buthidae scorpions Leiurus quinquestriatus and A. australis. Thus, according to a multiple sequence alignment using CLUSTAL, these new toxins seem to be related to the scorpion defensins.

Amino Acid Sequence↗

PubMed1999

Inhibition of HERG channels stably expressed in a mammalian cell line by the antianginal agent perhexiline maleate.

Perhexiline has been used as an anti-anginal agent for over 25 years, and is known to cause QT prolongation and torsades de pointes. We hypothesized that the cellular basis for these effects was blockade of I(Kr). A stable transfection of HERG into a CHO-K1 cell line produced a delayed rectifier, potassium channel with similar properties to those reported for transient expression in Xenopus oocytes. Perhexiline caused voltage- and frequency-dependent block of HERG (IC50 7.8 microM). The rate of inactivation was increased and there was a 10 mV hyperpolarizing shift in the voltage-dependence of steady-state inactivation, suggestive of binding to the inactivated state. In conclusion, perhexiline potently inhibits transfected HERG channels and this is the probable mechanism for QT prolongation and torsades de pointes. Channel blockade shows greatest affinity for the inactivated state.

Algorithms↗

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↗