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PubMed1995

Immunohistochemical localization of five members of the Kv1 channel subunits: contrasting subcellular locations and neuron-specific co-localizations in rat brain.

A large variety of potassium channels is involved in regulating integration and transmission of electrical signals in the nervous system. Different types of neurons, therefore, require specific patterns of potassium channel subunits expression and specific regulation of subunit coassembly into heteromultimeric channels, as well as subunit-specific sorting and segregation. This was investigated by studying in detail the expression of six different alpha-subunits of voltage-gated potassium channels in the rat hippocampus, cerebellum, olfactory bulb and spinal cord, combining in situ hybridization and immunocytochemistry. Specific polyclonal antibodies were prepared for five alpha-subunits (Kv1.1, Kv1.2, Kv1.3 Kv1.4, Kv1.6) of the Shaker-related subfamily of rat Kv channels, which encode delayed-rectifier type and rapidly inactivating A-type potassium channels. Their distribution was compared to that of an A-type potassium channel (Kv3.4), belonging to the Shaw-related subfamily of rat Kv channels. Our results show that these Kv channel alpha-subunits are differentially expressed in rat brain neurons. We did not observe in various neurons a stereotypical distribution of Kv channel alpha-subunits to dendritic and axonal compartments, but a complex differential subcellular subunit distribution. The different Kv channel subunits are targeted either to presynaptic or to postsynaptic domains, depending on neuronal cell type. Thus, distinct combinations of Kv1 alpha-subunits are co-localized in different neurons. The implications of these findings are that both differential expression and assembly as well as subcellular targeting of Kv channel alpha-subunits may contribute to Kv channel diversity and thereby to presynaptic and postsynaptic membrane excitability.

Animals↗
PubMedDate not supplied

Role of multiple calcium and calcium-dependent conductances in regulation of hippocampal dentate granule cell excitability.

We have constructed a detailed model of a hippocampal dentate granule (DG) cell that includes nine different channel types. Channel densities and distributions were chosen to reproduce reported physiological responses observed in normal solution and when blockers were applied. The model was used to explore the contribution of each channel type to spiking behavior with particular emphasis on the mechanisms underlying postspike events. T-type calcium current in more distal dendrites contributed prominently to the appearance of the depolarizing after-potential, and its effect was controlled by activation of BK-type calcium-dependent potassium channels. Coactivation and interaction of N-, and/or L-type calcium and AHP currents present in somatic and proximal dendritic regions contributed to the adaptive properties of the model DG cell in response to long-lasting current injection. The model was used to predict changes in channel densities that could lead to epileptogenic burst discharges and to predict the effect of altered buffering capacity on firing behavior. We conclude that the clustered spatial distributions of calcium related channels, the presence of slow delayed rectifier potassium currents in dendrites, and calcium buffering properties, together, might explain the resistance of DG cells to the development of epileptogenic burst discharges.

4-Aminopyridine↗
PubMed1994

Axolemmal and septal conduction in the impedance of the earthworm medial giant nerve fiber.

Ionic conduction in the axolemmal and septal membranes of the medial giant fiber (MGF) of the earthworm (EW) Lumbricus terrestris was assessed by impedance spectroscopy in the frequency range 2.5-1000 Hz. Impedance loci in the complex plane were described by two semi-circular arcs, one at a lower characteristic frequency (100 Hz) and the other at a higher frequency (500 Hz). The lower frequency arc had a chord resistance of 53 k omega and was not affected by membrane potential changes or ion channel blockers [tetrodotoxin (TTX), 3,4-diaminopyridine (3,4-DAP), 4-aminopyridine (4-AP), and tetraethylammonium (TEA)]. The higher frequency arc had a chord resistance of 274 k omega at resting potential, was voltage-dependent, and was affected by the addition of TTX, 3,4-DAP, 4-AP, and TEA to the physiological EW salines. When all four blockers were added to the bathing solution, the impedance locus was described by two voltage-independent arcs. Considering the effects of these and other (i.e., Cd and Ni) ion channel blockers, we conclude that: 1) the higher frequency locus reflects conduction by voltage-sensitive ion channels in the axolemmal membrane, which contains at least four ion channels selective for sodium, calcium, and potassium (delayed rectifier and calcium-dependent), and 2) the lower frequency locus reflects voltage-insensitive channels in the septal membrane, which separates adjacent MGFs.

4-Aminopyridine↗
PubMed1995

[Mechanisms of action of class III anti-arrhythmia agents].

Vaughan-Williams class III antiarrhythmic agents act mainly by prolonging the duration of the cardiac action potential and, thus, the refractory period. This effect may be obtained: 1) by increasing the inward sodium or calcium currents, which may lead to an intracellular calcium overload and induce a very proarrhythmic situation, or 2) by decreasing the outward potassium currents, the objective of the new class III antiarrhythmic drugs under development. They selectively block one or several potassium channels regulated by the membrane potential (transient outward current Ito, delayed rectifying current IK and rectifying inward current IK1). Under physiological conditions the blockade of potassium channels regulated by a ligand (for example, ATP-dependent) does not lead to a class III effect. Prolongation of ventricular repolarisation is accompanied by a slowing of the heart rate and a positive inotropic effect. It is attenuated by rapid rhythms and amplified by slow rhythms: this is the reverse frequency-dependent phenomenon. However, normal frequency dependence (or "use-dependence") has been reported with the ionic channel, this paradox apparently being related to the complexity of the relations between the relative contributions of the ionic currents of repolarisation and their modulation by the heart rate. The class III effect confers a proarrhythmic potential and may lead to torsades de pointes, favorised by bradycardia, hypokalaemia and hypomagnesaemia. Experimentally, it favorises early after depolarisations which are presumed to be the cellular trigger event. The comprehension of factors influencing the antiarrhythmic and proarrhythmic class III effects has led to the establishment of a pharmacological profile of the "ideal" drug conferring the least proarrhythmic risk and the best efficacy.

Action Potentials↗
PubMed1993

Potassium channels in airway smooth muscle: a tale of two channels.

Potassium channels are an important determinant of smooth muscle excitability and force generation. Two potassium channels have been fully described in airway smooth muscle: large conductance, calcium-activated potassium channels and voltage-dependent delayed rectifier channels. This article will review the biophysics and pharmacology of these channels and discuss what is currently known with respect to their regulation and physiological significance.

Adrenergic beta-Agonists↗
PubMed2001

A novel long-QT 5 gene mutation in the C-terminus (V109I) is associated with a mild phenotype.

Mutations in the human minK gene KCNE1 have been linked to autosomal dominant and autosomal recessive long-QT (LQT) syndrome, a cardiac condition predisposing to ventricular arrhythmias. minK and KvLQT1, the LQT1 gene product, form a native cardiac K+ channel that regulates the slowly delayed rectifier potassium current I(Ks). We used single-strand conformation polymorphism and sequencing techniques to identify novel KCNE1 mutations in patients with a congenital LQT syndrome of unknown genetic origin. In 150 unrelated index patients a missense mutation (V109I) was identified that significantly reduced the wild-type I(Ks) current amplitude (by 36%) when coexpressed with KvLQT1 in Xenopus oocytes. Other biophysical properties of the I(Ks) channel were not altered. Since we observed incomplete penetrance (only one of two mutation carriers could be diagnosed by clinical criteria), and the family's history was unremarkable for sudden cardiac death, the 109I allele most likely causes a mild phenotype. This finding may have implications for the occurrence of "acquired" conditions for ventricular arrhythmias and thereby the potential cardiac risk for asymptomatic mutation carriers still remains to be determined.

Alleles↗
PubMed2000

Electrophysiologic effects of lercanidipine on repolarizing potassium currents.

Blockade of cardiac repolarizing potassium channels by drugs may result in QT-interval prolongation, eventually degenerating into "torsades de pointes," a life-threatening arrhythmia. Lercanidipine (LER) is a recently introduced lipophilic calcium antagonist with no cardiodepressant activity and long-lasting antihypertensive action. Its chemical structure is characterized by the presence of a diphenylpropylaminoalkyl group, which is present in some of the drugs that have been reported to cause QT-interval prolongation. Our previous data demonstrated that LER blocks L-type calcium channels without affecting sodium current; however, no data are available concerning its effects on cardiac potassium channels. Transient outward (I(to)), delayed rectifier (I(K)), background currents, and action potential (AP) profile were measured from patch-clamped ventricular myocytes isolated from rat, guinea pig, or human hearts using enzymatic dissociation procedures. LER did not affect I(K) (and I(Kr)) density and activation curve in guinea pig myocytes; the reversal potential of the background current (I(K1)) and its slope were not changed by the drug. Maximal diastolic potential (MDP) and duration of the AP measured at -60 mV (APD(-60)) were not significantly changed. I(to) density and activation curves measured in rat myocytes were similar in the absence and presence of 1 or 10 microM LER. Finally, the effect of LER was tested in human ventricular myocytes: superfusion with 1 microM LER did not affect MDP and APD(-60). I(to) density and the midpoint of activation and inactivation curves were similar in the absence and presence of LER. In conclusion, our data demonstrate that LER does not affect repolarizing potassium currents and action potential profile recorded from guinea pig, rat, and human ventricular myocytes. It is unlikely that LER could cause QT prolongation in vivo.

Action Potentials↗
PubMed1998

Characterization of an eag-like potassium channel in human neuroblastoma cells.

1. SH-SY5Y human neuroblastoma cells were investigated with whole-cell and perforated patch recording methods. 2. Besides a quickly activating delayed rectifier channel and a HERG-like channel, a slowly activating potassium channel with biophysical properties identical to those of rat eag (r-eag) channels was detected, here referred to as h-eag. 3. h-eag shows a marked Cole-Moore shift, i.e. the activation kinetics become very slow when the depolarization starts from a very negative holding potential. In addition, extracellular Mg2+ and Ni2+ strongly slow down activation. 4. Application of acetylcholine induces a fast block of the current when recorded in the perforated patch mode. This block is presumably mediated by Ca2+, as about 1 microM intracellular Ca2+ completely abolished h-eag outward current. 5. When cells were grown in the presence of 10 microM retinoic acid in order to synchronize the cell line in the G1 phase of the cell cycle, h-eag current was reduced to less than 5 % of the control value, while the delayed rectifier channel was expressed more abundantly. Down-regulation of h-eag by long-term exposure to retinoic acid was paralleled by a right shift in the activation potential of HERG-like channels. 6. Acute application of 10 microM retinoic acid blocked the delayed rectifier channel but enhanced the h-eag current. 7. Thus, our results show that human neuroblastoma cells express in a cell cycle-dependent manner an [Mg2+]o-dependent potassium channel (h-eag) which is blocked by submicromolar concentrations of intracellular Ca2+.

Acetylcholine↗
PubMed2000

Muscle and motor-skill dysfunction in a K+ channel-deficient mouse are not due to altered muscle excitability or fiber type but depend on the genetic background.

The voltage-gated K+ channel Kv3.1 is expressed in skeletal muscle and in GABAergic interneurons in the central nervous system. Hence, the absence of Kv3.1 K+ channels may lead to a phenotype of myogenic or neurogenic origin, or both. Kv3.1-deficient (Kv3.1-/-) 129/Sv mice display altered contractile properties of their skeletal muscles and show poor performance on a rotating rod. In contrast, Kv3.1-/- mice on the (129/Sv x C57BL/6)F1 background display normal muscle properties and perform like wild-type mice. The correlation of poor performance on the rotating rod with altered muscle properties supports the notion that the skeletal muscle dysfunction in Kv3.1-/- 129/Sv mice may be responsible for the impaired motor skills on the rotating rod. Surprisingly, we did not find major differences between wild-type and Kv3.1-/- 129/Sv skeletal muscles in either the resting or action potential, the delayed-rectifier potassium conductance (gK) or the distribution of fast and slow muscle fibers. These findings suggest that the Kv3.1 K+ channel may not play a major role in the intrinsic excitability of skeletal muscle fibers although its absence leads to slower contraction and relaxation and to smaller forces in muscles of 129/Sv Kv3.1-/- mice.

Action Potentials↗
PubMed2006

Inhibition of cardiac HERG potassium channels by antidepressant maprotiline.

Many drugs block delayed rectifier K+ channels and prolong the cardiac action potential duration. Here we investigate the molecular mechanisms of voltage-dependent block of human ether-a-go-go-related gene (HERG) K+ channels expressed in cells HEK-293 and Xenopus oocytes by maprotiline. The IC50 determined at 0 mV on HERG expressed HEK-293 cell and oocytes was 5.2 and 23.7 microM, respectively. Block of HERG expressed in oocytes by maprotiline was enhanced by progressive membrane depolarization and accompanied by a negative shift in the voltage dependence of channel activation. The potency of maprotiline was reduced 7-fold by point mutation of a key aromatic residue (F656T) and 3-fold for Y652A, both located in the S6 domain. The mutation Y652A inverted the voltage dependence of HERG channel block by maprotiline. Together, these results suggest that voltage-dependent block of HERG results from gating dependent changes in the accessibility of Y652, a critical component of the drug binding site.

Animals↗
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↗
PubMed2005

Single-nucleotide polymorphisms of the KCNS3 gene are significantly associated with airway hyperresponsiveness.

Airway hyperresponsiveness (AHR) is one of the major clinical symptoms and intermediate phenotypes of asthma. A recent genome-wide search for asthma quantitative trait loci has revealed a significant linkage signal between a p-terminal region of chromosome 2 and AHR. Thus, the gene encoding the potassium voltage-gated channel delayed-rectifier protein S3 (KCNS3) in this region is considered a positional candidate for asthma. We have evaluated a total of 12 single-nucleotide polymorphisms (SNPs) of the KCNS3 gene in a validation panel of 48 lymphoblastoid cell line DNA samples of Chinese origin. Three SNPs were found to be polymorphic and were tested. Two independent sets (an initial screening set and a replication set) of cases and controls from the original linkage study sample were collected. In the initial screening set, two SNPs (rs1031771 and rs1031772) showed suggestive association and were further confirmed by the replication set. In combined single-SNP analysis, the rs1031771 G allele (odds ratio=1.42, P=0.006) and rs1031772 T allele (odds ratio=1.40, P=0.018) were associated with a significantly higher risk of AHR. Haplotype analysis also detected significant association (P=0.006). Our findings suggest that SNPs located at the 3' downstream region of KCNS3 have a significant role in the etiology of AHR.

Adult↗
PubMed1996

Inhibition of potassium currents by the antiarrhythmic drug E4031 in rat taste receptor cells.

The effect of the class III antiarrhythmic agent E4031 was investigated on a non-cardiac preparation as a potential tool for studying potassium currents. Patch clamp recordings in the whole cell configuration were performed on dissociated rat taste cells. These cells possess a variety of potassium currents; they also conduct action potentials. Unlike its more specific action on a type of delayed rectifier channel in cardiac cells, three types of potassium currents were reversibly diminished in taste cells in the presence of E4031. These included transient, sustained, and inwardly-rectifying potassium currents. Activation properties were not altered but the inactivation curve was shifted to the left by approximately 10 mV. Inhibitions of whole cell currents were voltage-dependent, larger at depolarized potentials, but were never complete. E4031 significantly broadened the gustatory action potential and, at higher concentrations, inhibited spike height, suggesting an additional inhibitory effect on sodium channels that was evident in voltage-clamp records. We conclude that E4031 is an effective inhibitor of potassium currents in the micromolar range and that it likely acts at a conserved segment of the potassium channel.

Action Potentials↗
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↗
PubMed1996

Preconditioning is not abolished by the delayed rectifier K+ blocker dofetilide.

ATP-sensitive potassium channels are thought to play an important role in preconditioning. possibly due to shortening of the action potential duration (APD). The purpose of this study was to determine the effect of the class III antiarrhythmic agent dofetilide on preconditioning at a dose that abolishes APD shortening during ischemia A pilot study was performed to find a dose of dofetilide that would abolish the APD shortening effect of preconditioning Anesthetized dogs were subjected to 5-min coronary occlusion (or sham) and 10-min reperfusion followed by 60-min coronary occlusion. Monophasic action potentials were recorded periodically throughout the experiment. Significant APD shortening was observed during the 5- and 60-min ischemic periods, although preconditioning did not further enhance APD shortening during the prolonged ischemia. Dofetilide (1 mg/kg + 0.01 mg.kg-1.h-1 iv) abolished the APD shortening effect of ischemia. The effect of this dose of dofetilide on the protective action of preconditioning was then determined. Preconditioning significantly reduced infarct size expressed as a percentage of the area at risk compared with nonpreconditioned hearts. Dofetilide had no effect on infarct size when given to nonpreconditioned hearts. In addition, dofetilide did not alter the protective effect of preconditioning. No differences in collateral blood flow during ischemia were observed for any group. This study shows that the class III antiarrhythmic agent dofetilide does not abolish preconditioning and that the cardioprotective effect of preconditioning is independent of APD shortening below baseline values.

Action Potentials↗
PubMed2006

The functional HERG variant 897T is associated with Conn's adenoma.

OBJECTIVE: Aldosterone secreting adenomas (aldosteronomas) have an unknown molecular origin. Ion channel currents are involved in signal transduction leading to aldosterone synthesis and secretion. HERG (human-ether-a-go-go-related gene) encodes for a potassium channel responsible for the outward rectifying delayed current and it is mutation prone. When mutated it causes most of the familial forms of both long QT and short QT syndromes. Abnormal repolarization in glomerulosa cells might increase aldosterone secretion or induce a proliferative advantage. The aims of this study were to: (1) evaluate HERG expression in aldosteronomas; (2) search for HERG somatic mutations; and (3) determine whether there is any relationship between the common HERG functional variant (A2690C, leading from lysine 897 to threonine, K897T) and aldosteronoma. DESIGN AND METHODS: Aldosteronoma and blood samples from 17 patients were studied to evaluate HERG expression, full-length HERG complementary DNA sequencing, and genotyping for K897T alleles. The prevalence of HERG 897 alleles was also tested in a control population and a population consisting entirely of hypertensive individuals. RESULTS: HERG was expressed in all aldosteronomas analysed. HERG somatic mutations were not detected. The 897T variant of HERG was significantly more common among patients with aldosteronoma (897T allele 41%) than in patients with moderate-severe essential hypertension (897T allele 20%, P = 0.007) or in the control population (897T allele 12%, P < 0.0001). The 897T/T genotype was present in 24% of the aldosteronoma patients versus 7% (P = 0.040) and 3% (P = 0.001) in essential hypertension and in the control population, respectively. When the chi test was performed considering the three groups together, the significance was similar (for alleles P < 0.0001 and for genotypes P = 0.004). CONCLUSION: The common functional HERG variant 897T may predispose to the development of aldosteronoma.

Adrenocortical Adenoma↗
PubMed1995

Cholinergic inhibition of slow delayed-rectifier K+ current in guinea pig sino-atrial node is not mediated by muscarinic receptors.

We studied the effects of cholinergic agonists on slow delayed-rectifier K+ current (IKs) in isolated cells from the sino-atrial node (SAN) region of guinea pig heart, using patch-clamp procedures. Carbachol (5 nM to 10 microM) inhibited IKs in guinea pig SAN cells in the absence of previous beta-adrenergic stimulation and in cells pretreated with 8-(4-chlorophenylthio)-cAMP. Neither the muscarinic antagonist atropine nor the nicotinic antagonist hexamethonium antagonized carbachol inhibition of the current. Similar results were obtained with other cholinergic agonists. Cholinergic stimulation of the muscarinic K+ current was successfully antagonized by atropine in SAN cells where inhibition of IKs persisted. Therefore, the lack of antagonist effects on inhibition of IKs cannot be attributed to either an absence of muscarinic cholinoceptors on SAN cells or a loss of antagonist activity under our experimental conditions. These data demonstrate that cholinergic agonists, including the endogenous neurotransmitter acetylcholine, decrease the amplitude of IKs in guinea pig SAN cells via a non-muscarinic, non-nicotinic, cAMP-independent mechanism. Although the precise nature of this signal transduction pathway has not been elucidated, it is clearly different from those described for regulation of other nodal currents. Differential regulation of IKs in guinea pig SAN and ventricle cannot be attributed to higher basal adenylate cyclase activity in SAN cells. The inhibitory effect of carbachol on IKs was not additive with that of verapamil, a drug that is both an allosteric muscarinic antagonist and a potassium channel-blocking agent. Cholinergic agonists may inhibit IKs in SAN cells via a direct interaction with the SAN IKs channel.

Allosteric Regulation↗
PubMed2005

Isolation and characterization of I(Kr) in cardiac myocytes by Cs+ permeation.

Isolation of the rapidly activating delayed rectifier potassium current (I(Kr)) from other cardiac currents has been a difficult task for quantitative study of this current. The present study was designed to separate I(Kr) using Cs+ in cardiac myocytes. Cs+ have been known to block a variety of K+ channels, including many of those involved in the cardiac action potential such as inward rectifier potassium current I(K1) and the transient outward potassium current I(to). However, under isotonic Cs+ conditions (135 mM Cs+), a significant membrane current was recorded in isolated rabbit ventricular myocytes. This current displayed the voltage-dependent onset of and recovery from inactivation that are characteristic to I(Kr). Consistently, the current was selectively inhibited by the specific I(Kr) blockers. The biophysical and pharmacological properties of the Cs+-carried human ether-a-go-go-related gene (hERG) current were very similar to those of the Cs+-carried I(Kr) in ventricular myocytes. The primary sequence of the selectivity filter in hERG was in part responsible for the Cs+ permeability, which was lost when the sequence was changed from GFG to GYG, characteristic of other, Cs+-impermeable K+ channels. Thus the unique high Cs+ permeability in I(Kr) channels provides an effective way to isolate I(Kr) current. Although the biophysical and pharmacological properties of the Cs+-carried I(Kr) are different from those of the K+-carried I(Kr), such an assay enables I(Kr) current to be recorded at a level that is large enough and sufficiently robust to evaluate any I(Kr) alterations in native tissues in response to physiological or pathological changes. It is particularly useful for exploring the role of reduction of I(Kr) in arrhythmias associated with heart failure and long QT syndrome due to the reduced hERG channel membrane expression.

Animals↗