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PubMed2004

[Cardiac effects of antipsychotics: mechanism of arrhythmias and sudden cardiac death].

The review summarizes experimental and clinical data showing the cardiac side effects of antipsychotic drugs. Some antipsychotics may correlate with prolongation of QT interval, induce ventricular tachycardia, torsades de pointes, TdP, and sudden death. The author surveys the cellular actions of the drugs, the electrophysiological mechanisms and the recent data referring the drug's effects on ionic currents, mainly potassium currents. Most antipsychotics are associated with the inhibition of delayed rectifier K+ channels. Comparing the potency on K+ channel inhibition and the prolongation of the QT interval with the therapeutic plasma levels of the drugs, the difference between the inhibitory potency and the therapeutic dose is the highest in the case of quetiapine, olanzepine and risperidone, while thioridazine shows the smallest difference. All drugs that cause TdP prolong the QT interval and inhibit the K+ rectifier channel, but the relationship is not precise. Some additional cellular effects of particular agents, modulating conditions, factors (diseases, electrolytes disturbances, genetic damage, drug interactions) make the individual vulnerable to arrhythmia. The paper highlights drug interactions causing risk of arrhythmia during chronic treatment of psychiatric patients.

Action Potentials↗
PubMed1999

Inactivation of the ERG current in NG108-15 cells.

Differentiated NG108-15 neuroblastoma x glioma hybrid cells were whole-cell voltage clamped. The rate of inactivation of ERG (ether-à-go-go related gene) potassium channels was measured with a three-pulse protocol. Contamination with delayed rectifier current at positive potentials was avoided by using the selective ERG channel blocker E-4031. The curve relating time constant of inactivation tau to membrane potential V could be fitted by a Gauss curve. In a bath with 40 mM K(+), the curve peaked at V = -36 mV. Lowering [K(+)](o) decreased tau. At V = -20 mV, the average tau was 25.4 ms in 40 mM K(+), 20.6 ms in 6.5 mM K(+), and 15.0 ms in 0 mM K(+). This resembles the relation between tau and [K(+)](o) in ERG channels expressed in Xenopus oocytes.

Animals↗
PubMedDate not supplied

Cardiovascular safety of second-generation antihistamines.

Reports of serious cardiac arrhythmia associated with some second-generation antihistamines have prompted concern for their prescription. This article reviews the nature of the adverse events reported and concludes that the blockade of potassium channels, particularly the subtype responsible for the rapid component of the delayed rectifier current (IKr), is largely responsible for such adverse cardiac events. Consequently, antihistamines with little or no interaction with these channels are expected to have the greatest safety margin. The main cardiac arrhythmia of concern is that of torsades de pointes, a potentially fatal phenomenon characterized by prolonged ventricular depolarization that manifests as a prolonged QT interval and polymorphic ventricular tachycardia, with twisting of the QRS complexes. Based on pre-clinical and clinical evidence, it appears that loratadine, cetirizine, and fexofenadine are safe from cardiac arrhythmia via the IKr channel, whereas astemizole and terfenadine have a propensity to cause ventricular tachyarrhythmias.

Animals↗
PubMed2000

Structural determinants of KvLQT1 control by the KCNE family of proteins.

KvLQT1 is a Shaker-like voltage-gated potassium channel that when complexed with minK (KCNE1) produces the slowly activating delayed rectifier I(ks). The emerging family of KCNE1-related peptides includes KCNE1 and KCNE3, both of which complex with KvLQT1 to produce functionally distinct currents. Namely I(ks), the slowly activating delayed rectifier current, is produced by KvLQT1/KCNE1, whereas KvLQT1/KCNE3 yields a more rapidly activating current with a distinct constitutively active component. We exploited these functional differences and the general structural similarities of KCNE1 and KCNE3 to study which physical regions are critical for control of KvLQT1 by making chimerical constructs of KCNE1 and KCNE3. By using this approach, we have found that a three-amino acid stretch within the transmembrane domain is necessary and sufficient to confer specificity of control of activation kinetics by KCNE1 and KCNE3. Moreover, chimera analysis showed that different regions within the transmembrane domain control deactivation rates. Our results help to provide a basis for understanding the mechanism by which KCNE proteins control K(+) channel activity.

Amino Acid Sequence↗
PubMed1987

Dendrotoxin blocks potassium channels and slows sodium inactivation in Myxicola giant axons.

Dendrotoxin (DTX) is known to partially block delayed rectifier K+ channels and enhance neurotransmitter release, but no effects on Na+ channels have been reported. In voltage-clamped Myxicola axons DTX affected both the K+ and Na+ conductances. DTX blocked completely Myxicola K+ channels with a KD of 150 nM and induced slow K+ inactivation. DTX doubled the time constants for inactivation of conducting Na+ channels and gating charge immobilization without altering Na+ activation or the voltage- and time-dependent fast and slow Na+ inactivation induced by depolarizing prepulses. A selective effect on open Na+ channel inactivation provides additional evidence for kinetic models in which resting Na+ channels need not open before being inactivated.

Animals↗
PubMed1992

Contribution of delayed rectifier and inward rectifier to repolarization of the action potential: pharmacologic separation.

Outward potassium (K) currents contribute to the repolarization process of cardiac action potentials. There are, however, multiple K currents. Recently, two putatively specific K channel blockers have been developed as potential class III antiarrhythmic agents. E-4031 appears to block specifically a fast component of the delayed rectifier (IK), and RP 58866 is a reported inward rectifier current (IK1) blocker. In the present experiments, we examined the effects of E-4031 and RP 58866 on action potentials recorded from guinea pig papillary muscles to determine whether the properties of IK and IK1 measured in whole-cell experiments would be manifested in distinct effects. Both compounds prolonged the APD50 (action potential duration at 50% repolarization) and APD90 (action potential duration at 90% repolarization). However, RP 58866 did not significantly prolong the action potential at voltages of 0 mV and above, while E-4031 did. The results suggest that preferential IK1 block results in a change in action potential waveform that is distinct from that resulting from block of other outward K currents. This could thus be used as a simple first-pass screening tool in determining a preliminary mechanism of action of class III antiarrhythmics prior to more time-consuming but necessary whole-cell voltage clamp experiments.

Action Potentials↗
PubMed2001

External nickel blocks human Kv1.5 channels stably expressed in CHO cells.

We have investigated the actions of Nickel (Ni(2+)) on a human cardiac potassium channel (hKv1.5), the main component of human atrial ultra-rapid delayed rectifier current, stably expressed in Chinese hamster ovary cell line using the whole-cell voltage-clamp technique. External Ni(2+) reversibly decreased the amplitude of the current in a concentration-dependent manner. The concentration for half-maximum inhibition of the current at +50 mV was 568 microm. The activation, deactivation, reactivation kinetics of the current were not affected by Ni(2+). Block was not voltage-dependent but frequency-dependent block was apparent. The extent of channel block during the first pulse increased when the duration of exposure to Ni(2+), prior to channel activation, was prolonged indicating that Ni(2+) interacted with hKv1.5 in the closed state. The percentage of current remaining in presence of Ni(2+) decreased steeply over the range of steady-state channel inactivation, consistent with an enhanced block with increased inactivation. This suggests that Ni(2+) preferentially blocks nonconducting hKv1.5 channels, either in the resting or inactivated state in a concentration-dependent manner. The data indicate that the mechanisms of hKv1.5 channel inhibition by Ni(2+) are distinct from those of other K(+) channels.

Animals↗
PubMed1990

Gating mechanism of a cloned potassium channel expressed in frog oocytes and mammalian cells.

We have cloned a cDNA coding for a delayed rectifier K+ channel from rat brain (RCK1) and rat muscle (RMK1) and expressed it in Xenopus oocytes and in a myoblast cell line (Sol-8). Stably transfected Sol-8 cells exhibited large outward K+ currents, which were indistinguishable from the K+ currents induced in Xenopus oocytes by injection of mRNA transcribed in vitro. RCK1 encodes a K+ channel with a unitary conductance of approximately 14 pS. The steep voltage dependence of channel opening resides in transitions between closed states, whereas the direct transitions into and out of the open state are very rapid and not markedly voltage-dependent. Channel inactivation is very slow, voltage-independent, and occurs from the open state only. We present a simple model that incorporates our findings and is consistent with the presumed structural symmetry of a functional K+ channel.

Animals↗
PubMed2002

[Evaluation of pro-arrhythmic risk of drugs due to QT interval prolongation by the HERG expression system].

Recently, there has been considerable attention focused on drugs that prolong the QT interval of the electrocardiogram. This occasionally evolves to fetal, polymorphic ventricular arrhythmias, torsades de pointes. Therefore, the early detection of the risk of drug-induced QT prolongation is important for avoiding the adverse cardiovascular effect in clinical use. It has been suggested that the QT prolongation and ventricular arrhythmia caused by drugs might be secondary to their ability to interfere with cardiac potassium channels involved in action potential repolarization and in particular with rapidly activating delayed rectifier K+ current (IKr). In cardiac myocytes, IKr contributes to termination of the plateau phase of action potential. The ether-a-go-go related gene in humans expressed a K+ channel current with biophysical characteristics similar to those of IKr. Electrophysiological studies on cloned HERG channels can provide fundamental information concerning the cardiac safety profile of new developing drugs.

Animals↗
PubMed1992

On the block of outward potassium current in rabbit Schwann cells by internal sodium ions.

Currents through delayed rectifier-type K+ channels in Schwann cells cultured from rabbit sciatic nerve were studied with patch-clamp techniques. When the internal and external solutions contained physiological concentrations of sodium, the amplitude of these outward currents declined as the cell was depolarized to potentials above about +40 mV, despite the increased driving force. This reduction in the amplitude of outward K+ currents was observed in many cells before the subtraction of leakage currents; it was also observed for ensemble currents recorded in outside-out patches. It was therefore not the result of a leak-subtraction artefact nor of inadequate voltage-clamp control. Several lines of evidence also suggested that it was not the result of the extracellular accumulation of K+. By contrast, when the Na+ ion concentration of the internal solution was nominally zero, the reduction in the amplitude of outward K+ currents at positive membrane potentials was not observed. The apparent amplitude of single-channel currents through two types of K+ channel was reduced by 30 mM internal Na+, apparently as the result of a rapid 'flickery' block. The results suggest that channel block by internal Na+ is largely responsible for the negative slope conductance seen in current-voltage plots of whole-cell K+ currents at positive membrane potentials. In addition, our analysis of single-channel currents suggests that the current-voltage curve for a delayed rectifier channel in rabbit Schwann cells (in the absence of internal Na+) is roughly linear with internal and external K+ concentrations of 140 mM and 5.6 mM, respectively.

Animals↗
PubMed2005

Specific serine proteases selectively damage KCNH2 (hERG1) potassium channels and I(Kr).

KCNH2 (hERG1) encodes the alpha-subunit proteins for the rapidly activating delayed rectifier K+ current (I(Kr)), a major K+ current for cardiac myocyte repolarization. In isolated myocytes I(Kr) frequently is small in amplitude or absent, yet KCNH2 channels and I(Kr) are targets for drug block or mutations to cause long QT syndrome. We hypothesized that KCNH2 channels and I(Kr) are uniquely sensitive to enzymatic damage. To test this hypothesis, we studied heterologously expressed K+, Na+, and L-type Ca2+ channels, and in ventricular myocytes I(Kr), slowly activating delayed rectifier K+ current (I(Ks)), and inward rectifier K+ current (I(K1)), by using electrophysiological and biochemical methods. 1) Specific exogenous serine proteases (protease XIV, XXIV, or proteinase K) selectively degraded KCNH2 current (I(KCNH2)) and its mature channel protein without damaging cell integrity and with minimal effects on the other channel currents; 2) immature KCNH2 channel protein remained intact; 3) smaller molecular mass KCNH2 degradation products appeared; 4) protease XXIV selectively abolished I(Kr); and 5) reculturing HEK-293 cells after protease exposure resulted in the gradual recovery of I(KCNH2) and its mature channel protein over several hours. Thus the channel protein for I(KCNH2) and I(Kr) is uniquely sensitive to proteolysis. Analysis of the degradation products suggests selective proteolysis within the S5-pore extracellular linker, which is structurally unique among Kv channels. These data provide 1) a new mechanism to account for low I(Kr) density in some isolated myocytes, 2) evidence that most complexly glycosylated KCNH2 channel protein is in the plasma membrane, and 3) new insight into the rate of biogenesis of KCNH2 channel protein within cells.

Animals↗
PubMed1998

[Inhibition of potassium channel by chronic hypoxia on pulmonary artery smooth muscle cells in rats].

OBJECTIVE: To explore the possible effect of potassium channel in chronic hypoxic pulmonary hypertension. METHOD: Male Wistar rats were placed in the identical normobaric or hypoxic environmental chamber. In one chamber, rats were maintained in 10% +/- 0.5% O2(by displacement with N2) for 3 weeks, whereas in the other, rats were maintained in air. The single smooth muscle cell was isolated from pulmonary artery (phi 200-700 microns) of Wistar rats with acute enzymatic digestion method. Using patch-clamp technique, we recorded the outward K+ currents in pulmonary artery smooth muscle cells and identified a Ca2+.ATP activated K+ channel (K+Ca-ATP) and a delayed rectifier K+ channel among the outward K+ currents. We compared the activities of Ca2+.ATP activated K+ channel (K+Ca-ATP) or delayed rectifier K+ channel in smooth muscle cells isolated from pulmonary artery of chronic hypoxic and normoxic rats. RESULT: The activities of Ca2+.ATP activated K+ channel (K+Ca-ATP) and delayed rectifier K+ channel in chronic hypoxic group are much lower than that in normal group (T test, P < 0.01). Cromakalim (10 mmol) caused a marked enhancement of activity of the reduced K+Ca-ATP but not the delayed rectifier K+ channel in rats of hypoxic group. CONCLUSION: The persistent decrease of potassium channel activity may contribute to setting the development of chronic hypoxic pulmonary hypertension. Cromakalim, one of potassium channel openers, can decrease the pulmonary hypertension induced by chronic hypoxia and may be a new effective drug for treatment of hypoxic pulmonary hypertension.

Animals↗
PubMed1987

Cation permeation through the voltage-dependent potassium channel in the squid axon. Characteristics and mechanisms.

Characteristics of cation permeation through voltage-dependent delayed rectifier K channels in squid giant axons were examined. Axial wire voltage-clamp measurements and internal perfusion were used to determine conductance and permeability properties. These K channels exhibit conductance saturation and decline with increases in symmetrical K+ concentrations to 3 M. They also produce ion- and concentration-dependent current-voltage shapes. K channel permeability ratios obtained with substitutions of internal Rb+ or NH+4 for K+ are higher than for external substitution of these ions. Furthermore, conductance and permeability ratios of NH+4 or Rb+ to K+ are functions of ion concentration. Conductance measurements also reveal the presence of an anomalous mole fraction effect for NH+4, Rb+, or Tl+ to K+. Finally, internal Cs+ blocks these K channels in a voltage-dependent manner, with relief of block by elevations in external K+ but not external NH+4 or Cs+. Energy profiles for K+, NH+4, Rb+, Tl+, and Cs+ incorporating three barriers and two ion-binding sites are fitted to the data. The profiles are asymmetric with respect to the center of the electric field, have different binding energies and electrical positions for each ion, and (for K+) exhibit concentration-dependent barrier positions.

Animals↗
PubMed1998

Episodic ataxia type-1 mutations in the hKv1.1 cytoplasmic pore region alter the gating properties of the channel.

Episodic ataxia type-1 is a rare human neurological syndrome which occurs during childhood and persists through the whole life of affected patients. Several heterozygous point mutations have been found in the coding sequence of the voltage-gated potassium channel gene hKv1.1 of different affected families. V408A and E325D mutations are located in the cytoplasmic putative pore region of hKv1.1 channels and profoundly alter their gating properties. V408A channels showed increased kinetic rates of activation, deactivation and C-type inactivation. Expression of E325D channels in Xenopus oocytes led to an approximately 13-fold current amplitude reduction and to a 52.4 mV positive shift in the voltage dependence of activation. Moreover, the E325D mutation altered the kinetics of activation, deactivation, C-type inactivation and channel open probability. Heteromeric channels composed of two wild-type and two mutated subunits, linked as dimers, showed gating properties intermediate between channels formed from four normal or four mutated subunits. The results demonstrate that the highly conserved residues Val408 and Glu325 play a pivotal role in several gating processes of a human potassium channel, and suggest a pathogenetic mechanism by which the impairment of the delayed-rectifier function of affected neurons is related to the type and number of mutated subunits which make up the hKv1.1 channels.

Animals↗
PubMed1988

Potassium conductance of the squid giant axon. Single-channel studies.

The patch-clamp technique was implemented in the cut-open squid giant axon and used to record single K channels. We present evidence for the existence of three distinct types of channel activities. In patches that contained three to eight channels, ensemble fluctuation analysis was performed to obtain an estimate of 17.4 pS for the single-channel conductance. Averaged currents obtained from these multichannel patches had a time course of activation similar to that of macroscopic K currents recorded from perfused squid giant axons. In patches where single events could be recorded, it was possible to find channels with conductances of 10, 20, and 40 pS. The channel most frequently encountered was the 20-pS channel; for a pulse to 50 mV, this channel had a probability of being open of 0.9. In other single-channel patches, a channel with a conductance of 40 pS was present. The activity of this channel varied from patch to patch. In some patches, it showed a very low probability of being open (0.16 for a pulse to 50 mV) and had a pronounced lag in its activation time course. In other patches, the 40-pS channel had a much higher probability of being open (0.75 at a holding potential of 50 mV). The 40-pS channel was found to be quite selective for K over Na. In some experiments, the cut-open axon was exposed to a solution containing no K for several minutes. A channel with a conductance of 10 pS was more frequently observed after this treatment. Our study shows that the macroscopic K conductance is a composite of several K channel types, but the relative contribution of each type is not yet clear. The time course of activation of the 20-pS channel and the ability to render it refractory to activation only by holding the membrane potential at a positive potential for several seconds makes it likely that it is the predominant channel contributing to the delayed rectifier conductance.

Animals↗
PubMed1989

Nonstationary fluctuation analysis of the delayed rectifier K channel in cardiac Purkinje fibers. Actions of norepinephrine on single-channel current.

We have studied the large increase in macroscopic potassium channel current caused by catecholamines in mammalian cardiac cells. An increase in macroscopic K current could result from either an increase in the single-channel current or by an increase in the number of channels that are open. Therefore, we have measured nonstationary potassium current fluctuations under voltage clamp conditions to determine whether norepinephrine increases the current through this channel. The single-channel current (at a potential of -30 mV in 4 mM external [K]) was estimated to be 3.7 pA and was not altered by concentrations of norepinephrine up to 2 microM. The spectral density of the current fluctuations were fitted well by a sum of 2 Lorentzians with corner frequencies that correspond with the measured time constants for deactivation of the macroscopic K current tails. We conclude that the increase in macroscopic K current caused by norepinephrine in these cells is not the result of an increase in single-channel conductance and therefore must involve an increase in the number of open K channels.

Animals↗
PubMed1998

Sea anemone peptides with a specific blocking activity against the fast inactivating potassium channel Kv3.4.

Sea anemone venom is known to contain toxins that are active on voltage-sensitive Na+ channels, as well as on delayed rectifier K+ channels belonging to the Kv1 family. This report describes the properties of a new set of peptides from Anemonia sulcata that act as blockers of a specific member of the Kv3 potassium channel family. These toxins, blood depressing substance (BDS)-I and BDS-II, are 43 amino acids long and differ at only two positions. They share no sequence homologies with other K+ channel toxins from sea anemones, such as AsKS, AsKC, ShK, or BgK. In COS-transfected cells, the Kv3.4 current was inhibited in a reversible manner by BDS-I, with an IC50 value of 47 nM. This inhibition is specific because BDS-I failed to block other K+ channels in the Kv1, Kv2, Kv3, and Kv4 subfamilies. Inward rectifier K+ channels are also insensitive to BDS-I. BDS-I and BDS-II share the same binding site on brain synaptic membranes, with K0.5 values of 12 and 19 nM, respectively. We observed that BDS-I and BDS-II have some sequence homologies with other sea anemone Na+ channels toxins, such as AsI, AsII, and AxI. However, they had a weak effect on tetrodotoxin-sensitive Na+ channels in neuroblastoma cells and no effect on Na+ channels in cardiac and skeletal muscle cells. BDS-I and BDS-II are the first specific blockers identified so far for the rapidly inactivating Kv3.4 channel.

Amino Acid Sequence↗
PubMed2004

K+ channels and their modulation by 5-HT in Drosophila photoreceptors: a modelling study.

In order to clarify the role of inactivating and noninactivating K+ conductances in nonspiking neurons, we developed an isopotential model of the Drosophila photoreceptor membrane based on Hodgkin-Huxley-type equations. The model includes voltage dependent potassium conductances, the shaker (gKA) and the delayed rectifier (gKs). The model parameters were derived from published results by Hardie and coworkers and nearly identical model was used also in our previous work (J. E. Niven, M. Vähäsöyrinki, M. Kauranen, R. C. Hardie, M. Juusola, and M. Weckström. The Contribution of shaker K+ channels to the information capacity of Drosophila photoreceptors. Nature. 421:630-634, 2003). The model explains how the two types of channels function together to define the voltage dependent properties of the photoreceptor membrane. Additionally the model enables us to run simulations of conditions which are difficult to achieve in patch clamp, like prolonged membrane depolarizations by light adaptation. Effects of the activation of the delayed rectifier type conductance were found to be in accordance with published experimental work but the inactivation of the shaker channels, in addition to its importance in the determination of the resting potential, produced voltage amplification over equivalent passive membrane under dark adapted conditions. This phenomenon was not present in light adapted conditions. The modulation of the voltage dependence of the conductances as reported by serotonin (5-HT) caused the shaker to act essentially like the delayed rectifier conductance.

Animals↗