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PubMed2005

Endogenous KCNE subunits govern Kv2.1 K+ channel activation kinetics in Xenopus oocyte studies.

Kv2.1 is a voltage-gated potassium (Kv) channel that generates delayed rectifier currents in mammalian heart and brain. The biophysical properties of Kv2.1 and other ion channels have been characterized by functional expression in heterologous systems, and most commonly in Xenopus laevis oocytes. A number of previous oocyte-based studies of mammalian potassium channels have revealed expression-level-dependent changes in channel properties, leading to the suggestion that endogenous oocyte factors regulate channel gating. Here, we show that endogenous oocyte potassium channel KCNE ancillary subunits xMinK and xMiRP2 slow the activation of oocyte-expressed mammalian Kv2.1 channels two-to-fourfold. This produces a sigmoidal relationship between Kv2.1 current density and activation rate in oocyte-based two-electrode voltage clamp studies. The effect of endogenous xMiRP2 and xMinK on Kv2.1 activation is diluted at high Kv2.1 expression levels, or by RNAi knockdown of either endogenous subunit. RNAi knockdown of both xMiRP2 and xMinK eliminates the correlation between Kv2.1 expression level and activation kinetics. The data demonstrate a molecular basis for expression-level-dependent changes in Kv channel gating observed in heterologous expression studies.

Animals↗
PubMed2001

Molecular biology of K(+) channels and their role in cardiac arrhythmias.

The configuration of cardiac action potentials varies considerably from one region of the heart to another. These differences are caused by differential cellular expression of several types of K(+) channel genes. The channels encoded by these genes can be grouped into several classes depending on the stimulus that permits the channels to open and conduct potassium ions. K(+) channels are activated by changes in transmembrane voltage or binding of ligands. Voltage-gated channels are normally the most important players in determining the shape and duration of action potentials and include the delayed rectifiers and the transient outward potassium channels. Ligand-gated channels include those that probably have only minor roles in shaping repolarization under normal conditions but, when activated by extracellular acetylcholine or a decrease in the intracellular concentration of ATP, can substantially shorten action potential duration. Inward rectifier K(+) channels are unique in that they are basically stuck in the open state but can be blocked in a voltage-dependent manner by intracellular Mg(2+), Ca(2+), and polyamines. Other K(+) channels have been described that provide a small background leak conductance. Many of these cardiac K(+) channels have been cloned in the past decade, permitting detailed studies of the molecular basis of their function and facilitating the discovery of the molecular basis of several forms of congenital arrhythmias. Drugs that block cardiac K(+) channels and prolong action potential duration have been developed as antiarrhythmic agents. However, many of these same drugs, as well as other common medications that are structurally unrelated, can also cause long QT syndrome and induce ventricular arrhythmia.

Animals↗
PubMed2000

Inhibition of delayed rectifier K+ conductance in cultured rat cerebellar granule neurons by activation of calcium-permeable AMPA receptors.

Activation of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors in cerebellar granule cells during perforated-patch whole-cell recordings activated an inward current at negative voltages which was followed, after a delay, by the inhibition of an outward potassium current at voltages positive to -20 mV. The activated inward current was inwardly rectifying suggesting that the AMPA receptors were Ca2+-permeable. This was confirmed by direct measurements of intracellular calcium where Ca2+ rises were seen following AMPA receptor activation in Na+-free external solution. Ca2+ rises were equally large in the presence of 100 microM Cd2+ to block voltage-gated Ca2+ channels. Specific voltage-protocols, allowing selective activation of the delayed rectifier potassium current (KV) and the transient A current (KA), showed that kainate inhibited KV, but not to any great extent KA. The inhibition of KV was blocked by the AMPA receptor antagonist CNQX (6-cyano-7-nitroquinoxaline-2,3-dione) and was no longer observed when the KV current was abolished with high concentrations of Ba2+. The responses to kainate were not altered by pre-treating the cells with pertussis toxin, suggesting that the AMPA receptor stimulation of the G-protein Gi cannot account for the effects observed. Replacing extracellular Na+ with choline did not alter the inhibition of KV by kainate, however, removing extracellular Ca2+ reduced the kainate response. The inhibition of KV by kainate was unaffected by the presence of 100 microM Cd2+. The guanylyl cyclase inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), did not alter kainate inhibition of KV. It is concluded that ion influx (particularly Ca2+ ions) through AMPA receptor channels following receptor activation leads to an inhibition of KV currents in cerebellar granule neurons.

Animals↗
PubMed2005

[The genetic disorders responsible for sudden cardiac death].

Sudden cardiac death is defined as an unpredictable death within 24 hours. It is estimated to occur with a frequency of more than 50,000 per year in Japan. The inherited arrhythmogenic diseases associated with the transmembranous ionic channels, anchoring proteins or intracellular calcium regulating proteins are thought to be responsible for sudden cardiac death in infants, children, and young adults who have structurally normal hearts. Recent genetic analyses have identified congenital diseases such as the long-QT syndrome (LQTS), the Jervell and Lange-Nielsen syndrome (JLNS), the Brugada syndrome (BrS), the short-QT syndrome (SQTS), the arrhythmogenic right ventricular cardiomyopathy type 2 (ARVC2), and the catecholamine-induced polymorphic ventricular tachycardia (CPVT) /familial polymorphic ventricular tachycardia (FPVT). Loss of function in the slow component of the delayed rectifier potassium current (I(Ks)) channels (KCNQ1, KCNE1), the rapid component of the potassium current (I(Kr)) channels (KCNH2, KCNE2) and the inward rectifier potassium current (I(Kl), Kir2.1) channel (KCNJ2) is linked to the LQTSs (type 1, 2, 5, 6, and 7 (Andersen syndrome)) and the JLNSs (type 1 and 2). Changes of function in the alpha-subunit of cardiac sodium channels (SCN5A) is also linked to the LQTS type 3 and the BrS. A mutation in the ankyrin-B, anchoring proteins, has been identified as cause of the LQTS type 4. The SQTS is caused by gain of function in the KCNH2. Further, the missense mutations in the gene encoding ryanodine receptor 2 (RyR2) or calsequestrin 2 (CASQ2) that regulate intra-cardiac calcium handling is possibly implicated in the ARVC2 and the CPVT/FPVT. Herein, we present a review of the literature regarding the genetic mechanisms of the inherited arrhythmogenic diseases.

Adult↗
PubMed1991

Maturation of a transient outward potassium current in mouse fetal hypothalamic neurons in culture.

The whole-cell voltage clamp technique was used to record potassium currents in mouse fetal hypothalamic neurons developing in culture medium from days 1 to 17. The neurons were derived from fetuses of IOPS/OF1 mice on the 14th day of gestation. The mature neurons (greater than six days in culture) showed both a transient potassium current and a non-inactivating delayed rectifier potassium current. These were identified pharmacologically by using the potassium channel blockers tetraethyl ammonium chloride and 4-aminopyridine, and on the basis of their kinetics and voltage sensitivities. The delayed rectifier potassium current had a threshold of-20 mV, a slow time-course of activation, and was sustained during the voltage pulse. The 4-aminopyridine-sensitive current was transient, and was activated from a holding potential more negative (-80 mV) than that required for evoking the delayed rectifier potassium current (-40 mV). The delayed rectifier potassium current was detectable from day 1 onwards, while the transient potassium current showed a distinct developmental trend. The time-constant of inactivation became faster with age in culture. The half steady-state inactivation potential showed a shift towards less negative membrane potentials with age, and the relationship was best described by a logarithmic regression equation. The developmental trend of the transient potassium current may relate functionally to the progressive morphological changes, and the appearance of synaptic connections during ontogenesis.

Animals↗
PubMed2000

Effects of JTV-519, a novel anti-ischaemic drug, on the delayed rectifier K+ current in guinea-pig ventricular myocytes.

We studied the effects of a newly synthesized anti-ischaemic agent, 4-[3-(4-benzylpiperidin-1-yl) propionyl]-7-methoxy-2, 3, 4, 5-tetrahydro-1, 4-benzothiazepine monohydrochloride (JTV-519) on the delayed rectifier potassium current (IK), using guinea-pig ventricular myocytes and whole-cell voltage-clamp techniques, under blockade of the L-type calcium current (ICa,L) by D600 (1 microM) or nitrendipine (5 microM). The IK in guinea-pig ventricular cells consists of two different components; the rapidly activating, E4031-sensitive component (IKr) and the slowly activating E4031-resistant component (IKs). Under steady-state conditions, JTV-519 (1 and 5 microM) did not change the amplitude of IKs remaining after blockade of IKr with 5 microM E4031. The effect of JTV-519 on IKr was assessed using short (50 ms) pulses which evoked a tail current that was sensitive to E4031 but not to chromanol 293B, a specific blocker of IKs. JTV-519 suppressed the IKr with a half-maximal inhibitory concentration of 1.2 microM. Selective inhibition of IKr by this agent was confirmed by using the "envelope of tails" test. These results suggest that the blockade of IKr may underlie the prolongation of action potential duration in ventricular muscle and QT-intervals alleged to occur in animal as well as human hearts.

Action Potentials↗
PubMed2005

QT PRODACT: evaluation of the potential of compounds to cause QT interval prolongation by action potential assays using guinea-pig papillary muscles.

Certain compounds that prolong QT interval in humans have little or no effect on action-potential (AP) duration used traditionally, but they inhibit rapidly-activated-delayed-rectifier potassium currents (IKr) and/or human ether-a-go-go-related gene (hERG) currents. In this study using isolated guinea-pig papillary muscles, we investigated whether new parameters in AP assays can detect the inhibitory effects of various compounds on IKr and/or hERG currents with high sensitivity. The difference in AP duration between 60% and 30% repolarization, 90% and 60% repolarization, and 90% and 30% repolarization (APD30-60, APD60-90, and APD30-90, respectively) were calculated as the new parameters. All the 15 IKr and/or hERG current inhibitors that have been reported (9 compounds) or not reported (6 compounds) to inhibit calcium currents prolonged APD30-60, APD60-90, and/or APD30-90; and 8 of the 15 inhibitors prolonged APD30-60, APD60-90, and/or APD30-90 more potently than APD90. The APD30-60, APD60-90, and APD30-90 measurements revealed no difference in sensitivity when evaluating the effects of the IKr and/or hERG current inhibitors on the three parameters. On the other hand, compounds with little or no effect on hERG currents had no effect on APD30-60, APD60-90, or APD30-90. Therefore, it is concluded that in AP assays using isolated guinea-pig papillary muscles, APD30-60, APD60-90, and APD30-90 are useful indexes for evaluating the inhibitory effects of compounds including mixed ion-channel blockers on IKr and/or hERG currents.

Action Potentials↗
PubMed1996

Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart.

BACKGROUND: Sex hormones are known to exert direct and indirect effects on cardiovascular function, but their effects on cardiac repolarization have not been elucidated. The repolarization phase of the cardiac action potential or QT interval of the ECG is regulated largely by potassium channels such as the delayed rectifier currents HK2 and IsK. METHODS AND RESULTS: The effects of ovariectomy (OVX) and estradiol (E2) or dihydrotestosterone (DHT) treatment were evaluated on HK2, HERG, and IsK mRNA levels, QT duration, and quinidine-induced changes in QT interval in isolated rabbit hearts. HK2 and 0.7-kilobase IsK mRNA were downregulated in cardiac ventricular tissue from OVX rabbits treated with either E2 or DHT. The QT interval was prolonged in E2- and DHT-treated animals (OVX + vehicle, 223 +/- 6 ms; OVX + DHT, 236 +/- 10 ms; and OVX + DHT, 245 +/- 6 ms; P < .05). CONCLUSIONS: The association between hormone-induced changes in baseline QT interval and the mRNA level for these channels suggests that sex hormones may play a critical role in regulating cardiac repolarization. However, the changes in baseline QT and potassium channel mRNA after hormone treatment were not concordant with the changes in QT interval after the infusion of quinidine, after which E2-treated animals responded similarly to controls (18.4 +/- 4.6% and 19.3 +/- 4.6% increase in QT interval, respectively) and DHT-treated animals exhibited less QT prolongation (11.4 +/- 3.8% increase; P < .03).

Animals↗
PubMed2002

[Effects of chronic exposure to beta-amyloid-peptide25-35 on the mRNA expressions of voltage-gated outward potassium channel subunits in cultured rat hippocampal neurons].

AIM: To investigate mRNA expression changes of voltage-gated outward potassium channel subtypes in cultured rat hippocampal neurons after chronic exposure to beta-amyloid-petitde25-35 (beta-AP25-35). METHODS: mRNA expression was detected by RT-PCR, comparative expression levels were determined by imaging densitometer. RESULTS: Delayed rectifying (Kv2.1, Kv1.5), transient outward (Kv1.4, Kv4.2) and large conductance calcium-activated (rSlo) potassium channel mRNA were expressed in cultured rat hippocampal. In the presence of beta-AP25-35 3 mumol.L-1 for 24 h, the relative expression level of Kv2.1 was significantly increased (n = 3, P < 0.05); the other subtypes were not changed obviously (n = 3, P > 0.05). The increase of Kv2.1 mRNA mainly happened between 24 and 36 h after exposure to beta-AP25-35. After exposure to beta-AP25-35 for 60 h, Kv2.1 mRNA decreased significantly (n = 3, P < 0.01). CONCLUSION: The upregulation of Kv2.1 on transcription levels may be involved in the enhancement of delayed rectifying outward potassium (Ik) current induced by beta-AP25-35.

Amyloid beta-Peptides↗
PubMedDate not supplied

Quantitative structure-activity relationship studies on inhibition of HERG potassium channels.

The human ether-a-go-go-related gene (HERG) protein forms the ion channel responsible for the rapidly acting delayed rectifier potassium current, I(Kr), and its blockade is a significant contributor to prolongation of the QT interval. Using descriptors which have clear physicochemical meanings and are familiar to medicinal chemists, we have carried out 2D-quantitative structure-activity relationship (2D-QSAR) studies on 104 HERG channel blockers with diverse structures collected from the literature, and we have formulated interpretable models to guide chemical-modification studies and virtual screening. Statistically significant descriptors were selected by a genetic algorithm, and the final model included the octanol/water partition coefficient, topological polar surface area, diameter, summed surface area of atoms with partial charges from -0.25 to -0.20, and an indicator variable representing the experimental conditions. The statistics were r = 0.839, r2 = 0.704, q2 = 0.671, s = 0.763, and F = 46.6. The correspondence of the molecular determinants derived from the 2D-QSAR models with the 3D structural characteristics of the putative binding site in a homology-modeled HERG channel is also discussed.

Ether-A-Go-Go Potassium Channels↗
PubMed2002

Cardiotoxicity of new antihistamines and cisapride.

Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity.

Arrhythmias, Cardiac↗
PubMed2002

Anticonvulsant phenytoin affects voltage-gated potassium currents in cerebellar granule cells.

The anticonvulsant drug phenytoin (diphenylhydantoin, DPH) was examined for its action on potassium currents in cerebellar granule cells using the whole-cell patch-clamp technique. Granular cells expressed two main types of voltage-dependent potassium currents: the first, sensitive to Tetraethylammonium ion (TEA), resembles a delayed rectifier K(+) channel (I(d)); the second shows biophysical and pharmacological properties similar to an I(A)-type potassium current. Phenytoin blocks the I(A) current in a dose-dependent manner, with an apparent dissociation constant K(d) of (73+/-7) microM. The drug shifts the steady-state inactivation curves towards a more negative potential, stabilizing the inactivated state, while the activation kinetics remain unaffected. The estimated K(d) when the cell is held to -100 mV (closed state of the channel) is 145+/-8 microM which decreases to 35+/-10 microM at -80 mV holding potential (partial inactivation of the channel). Phenytoin shows a discriminant behaviour between the two different types of potassium channels because at high concentration the effect of the drug on the delayed rectifier K(+) channel is negligible.

Animals↗
PubMed1994

Genetics and molecular biology of the inherited long QT syndrome.

Two forms of the inherited long QT syndrome have been known for many years: the autosomal recessive Jervell and Lange-Nielsen form and the autosomal dominant Romano-Ward form. A gene marker at the 11p 15.5 locus has been identified for some, but not all, families with the autosomal dominant form, but as yet the gene has not been identified. It is apparent that mutations of at least four genes, and possibly more, can cause the syndrome. The molecular biology of the syndrome is not yet clarified, but abnormalities of ion channel function are likely, particularly the potassium delayed rectifier current. Proposals for the pathophysiology include an abnormality of a G protein which controls ion channel and adrenergic pathway function, as well as a disturbance of the sympathetic nervous system. The identification of the abnormal gene(s) and the gene products will provide precise information on the molecular physiology of the syndrome.

Animals↗
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↗