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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↗
PubMed1993

Use-dependent block of the pacemaker current I(f) in rabbit sinoatrial node cells by zatebradine (UL-FS 49). On the mode of action of sinus node inhibitors.

BACKGROUND: Zatebradine (UL-FS 49) is a drug with a specific bradycardiac electrophysiological profile. It reduces heart rate by lengthening the duration of diastolic depolarization in the sinoatrial (SA) node. The ionic basis of this action, however, is not clarified. METHODS AND RESULTS: We used the whole-cell patch-clamp technique to study the effects of zatebradine on ionic currents underlying diastolic depolarization of isolated rabbit SA node cells. Low concentrations of zatebradine simultaneously reduced diastolic depolarization rate and the pacemaker current I(f). The drug blocked the pacemaker current, I(f), in a use-dependent manner without causing a shift of its activation curve. At hyperpolarized potentials, unblock of I(f) occurred. Clinically relevant concentrations of the drug have little effect on the L-type calcium current or delayed rectifier potassium current. CONCLUSIONS: This use-dependent block of the If channel can account for most of the pharmacological characteristics of zatebradine and is probably the mechanism of heart rate reduction caused by this agent. Thus, the sinus node inhibitor zatebradine belongs to a new class of "I(f) blockers" with possible advantages over currently available drugs for the treatment of ischemic heart disease.

Animals↗
PubMed1996

Mechanism of cardiac inotropy by phenamil, and epithelial sodium channel blocker.

Phenamil, an amiloride derivative, is a potent inhibitor of epithelial type sodium channels and a relaxant of smooth muscle. In canine cardiac ventricular trabeculae, which do not express epithelial type sodium channels, phenamil produces positive inotropy and prolongs twitch duration. Sarcoplasmic reticulum does not appear to be essential for phenamil-induced inotropy, because cyclopiazonic acid and ryanodine do not abolish this effect. Furthermore, in tissues made to contract biphasically with 90 to 98% substitution of calcium with strontium, phenamil enhanced the second phase of the contraction which is transsarcolemmal-calcium dependent. Phenamil did not alkalinize or acidify the cytosol (measured with 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein, BCECF) during the induction of positive inotropy, therefore the sodium-hydrogen exchange is not affected. Sodium-calcium exchange, as assessed by twin rapid cooling contractures, was not inhibited by phenamil. Direct inhibition of this exchanger is therefore not necessary for the inotropic action of phenamil. Phenamil did not inhibit the sodium pump in smooth muscle. Unlike ouabagenin, it significantly prolonged the action potential duration at 90% repolarization. We have demonstrated recently that prolongation of cardiac action potential duration with phenamil is due to inhibition of the inwardly rectifying potassium current without any direct effect on cardiac calcium channels. The resulting delay in repolarization of the terminal part of the action potential reduces the driving force for the forward mode of sodium-calcium exchange. This indirectly reduces the activity of the sodium-calcium exchanger and slows the extrusion of calcium from the cell at the end of the action potential leading to a gradual development of positive inotropy.

Amiloride↗
PubMed1998

Potassium channels modulate hypoxic pulmonary vasoconstriction.

The role of Ca2+-activated K+-channel, ATP-sensitive K+-channel, and delayed rectifier K+-channel modulation in the canine pulmonary vascular response to hypoxia was determined in the isolated blood-perfused dog lung. Pulmonary vascular resistances and compliances were measured with vascular occlusion techniques. Under normoxia, the Ca2+-activated K+-channel blocker tetraethylammonium (1 mM), the ATP-sensitive K+-channel inhibitor glibenclamide (10(-5) M), and the delayed rectifier K+-channel blocker 4-aminopyridine (10(-4) M) elicited a small but significant increase in pulmonary arterial pressure. Hypoxia significantly increased pulmonary arterial and venous resistances and pulmonary capillary pressure and decreased total vascular compliance by decreasing both microvascular and large-vessel compliances. Tetraethylammonium, glibenclamide, and 4-aminopyridine potentiated the response to hypoxia on the arterial segments but not on the venous segments and also further decreased pulmonary vascular compliance. In contrast, the ATP-sensitive K+-channel opener cromakalim and the L-type voltage-dependent Ca2+-channel blocker verapamil (10(-5) M) inhibited the vasoconstrictor effect of hypoxia on both the arterial and venous vessels. These results indicate that closure of the Ca2+-activated K+ channels, ATP-sensitive K+ channels, and delayed rectifier K+ channels potentiate the canine pulmonary arterial response under hypoxic conditions and that L-type voltage-dependent Ca2+ channels modulate hypoxic vasoconstriction. Therefore, the possibility exists that K+-channel inhibition is a key event that links hypoxia to pulmonary vasoconstriction by eliciting membrane depolarization and subsequent Ca2+-channel activation, leading to Ca2+ influx.

4-Aminopyridine↗
PubMed1986

Is the K permeability of the resting membrane controlled by the excitable K channel?

To test whether or not the potassium permeability of the resting membrane is controlled by the excitable K channels (delayed rectifier), we examined changes in the Na and K permeability ratio, PNa/PK, of the squid axon before and after the excitable K channels were blocked. The blockage of the K channels was accomplished by three independent methods: internal application of tetraethylammonium, internal application of 4-aminopyridine plus Cs, and prolong internal perfusion of NaF solution. The permeability ratio was determined using two different methods: the conventional electrophysiological method and a new method based on the measurements of the hyperpolarizing effect of Na removal. We found that blocking the K channels did not cause a proportional decrease in the K permeability of the resting membrane, suggesting that the semipermeable property of the resting membrane is not determined by the excitable K channels.

Animals↗
PubMed1992

Identification of RBK1 potassium channels in C6 astrocytoma cells.

Ionic currents in C6 astrocytoma cells were studied using the patch clamp technique under the whole cell configuration. A delayed rectifier K+ current with an amplitude of approximately 1 nA at +50 mV was observed in 86% (92/107) of the cells examined. This K+ current resembled the delayed rectifier present in type-1 and type-2 astrocytes in vitro and could be inhibited by a variety of K+ channel blockers, including TEA (IC50:0.5 mM), 4-aminopyridine (IC50:0.2 mM), MCD peptide (IC50:52 nM), dendrotoxin I (IC50:9 nM), and charybdotoxin (74% inhibition at 50 nM). Northern blot analysis, cloning of cDNA and subsequent sequencing showed that the C6 cell delayed rectifier K+ channel is equivalent to the RBK1 K+ channel derived from a rat brain cDNA library. The level of RBK1 transcripts in C6 cells was comparable to that reported in rat brain. The C6 delayed rectifier K+ channel is probably a homomeric RBK1 K+ channel judging from its pharmacological properties which are similar to the RBK1 channel expressed in Xenopus oocytes. Some C6 cells also expressed a transiently activated outward K+ current (IA). This current was found in less than 50% of the cells and in general contributed no more than 8% of the total outward current. No voltage-dependent inward Na+ or Ca2+ currents or inwardly rectifying K+ currents were observed in over 100 C6 cells examined. The present results show that the dominant voltage gated ionic current in C6 cells is the RBK1 delayed rectifier K+ channel.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1970

Slow changes in potassium permeability in skeletal muscle.

1. Voltage clamp experiments on sartorius muscle fibres at 3 degrees C showed that the potassium current is divisible into three components, namely:(a) Current in the delayed rectifier channel, which reached a maximum in about 0.1 sec at -30 mV, and declined with a time constant of about 4 msec when the fibre was repolarized to -100 mV; this component had an approximately linear instantaneous current-voltage relation and an equilibrium potential E(1) at 10-15 mV positive to the resting potential.(b) A slow component which reached a maximum in about 3 sec at -30 mV, and declined with a time constant of about 0.5 sec when the fibre was repolarized to -100 mV; this component had an approximately linear instantaneous current-voltage relation and a mean equilibrium potential E(2) at -83 mV in fibres where E(1) averaged -75 mV.(c) Current in the inward rectifier channel which decreased with a time constant of about 0.25 sec when the fibre was hyperpolarized to -150 mV. This component had an equilibrium potential close to the resting potential and an instantaneous current-voltage relation which was that of an inward rectifier.2. The general characteristics of the late after-potential in muscles in hypertonic solutions at 3 degrees C are consistent with those of the slow conductance change. The sign of the late after-potentials was reversed by depolarizing below -80 mV.3. The decline of current during a maintained hyperpolarization cannot be attributed solely to a decrease in tubular potassium concentration, since there may be a large decrease in current without much alteration of equilibrium potential. The negative slope conductance often seen at -150 mV is also difficult to reconcile with the tubular depletion hypothesis.4. Replacement of 10 mM-K by 10 mM-Rb abolished inward rectification but had less effect on the fast and slow components of the potassium conductance.

Action Potentials↗
PubMed2005

Drug-induced QT interval prolongation--regulatory guidance and perspectives on hERG channel studies.

Drug-induced QT interval prolongation with or without Torsade de Pointes has led to the withdrawal, or severe prescribing restrictions being placed on the use, of many drugs. Other drugs have been denied regulatory approval because of their 'QT liability'. This mechanism-based toxicity results principally from inhibition of IKr, the rapid component of delayed rectifier potassium current. The KCNH2 (hERG) gene encodes the physiologically germane alpha-subunits of the channels that conduct this current. Among the battery of non-dinical tests used to characterize a drug for its 'QT liability' are the hERG channel studies. Studies with the hERG channel have been used for early screening of lead compounds and making 'go-no-go' decisions. However, the predictive value of these studies is limited by inter-laboratory variations, a high false-positive rate and lack of a consensus on the definition of a negative study ('safety margins'). From a regulatory perspective, it is reassuring that clinical torsadogens have always been hERG positive with no false negatives. hERG channel studies are useful in guiding electrocardiographic safety monitoring in early human studies, evaluating the relative risks of metabolites and enantiomers of a drug and clarifying uncertain mechanisms of action. One emerging issue of concern is the effect of drugs on hERG trafficking. Classical hERG channel studies will not identify these drugs. For adequate risk assessment, hERG channel data should be integrated with all other non-clinical and clinical data; otherwise there is a risk of novel and valuable drugs being rejected from development and/or denied regulatory approval.

Action Potentials↗
PubMed1993

Levcromakalim may induce a voltage-independent K-current in rat portal veins by modifying the gating properties of the delayed rectifier.

1. Smooth muscle cells of the rat portal vein were dispersed by enzymatic treatment and recordings of whole-cell currents under calcium-free conditions were made by the voltage-clamp technique. The effects of the potassium (K)-channel opener, levcromakalim, on K-currents were compared with those of agents which modify protein phosphorylation. 2. Levcromakalim (1-10 microM) added to the extracellular (bath) fluid caused the development of a non-inactivating current (IK(ATP)) and simultaneously inhibited the delayed rectifier current (IK(V)) in a concentration-dependent manner. On prolonged exposure to levcromakalim (10 microM), IK(ATP) declined and IK(V) was further diminished. 3. Addition to the pipette (intracellular) solution of the selective inhibitor of protein kinase C, calphostin C, itself had no effect on K-currents and did not modify the induction of IK(ATP) or the simultaneous inhibition of IK(V) produced by 1 microM levcromakalim. 4. Addition of the protein kinase inhibitor (PKI(6-22)amide, 1 microM) to the pipette solution caused the production of a glibenclamide-sensitive, non-inactivating current and inhibited IK(V). 5. In an assay system, levcromakalim (10 microM) did not inhibit the activity of purified protein kinase A (Type 1 or Type 2). 6. Addition to the pipette solution of the phosphatase inhibitor, okadaic acid (1 microM), did not itself modify K-currents and had little effect on the simultaneous induction of IK(ATP) and inhibition of IK(V) by levcromakalim (1 microM). 7. When the pipette solution contained 1 mM MgATP (but was depleted of substrates for ATP production), a non-inactivating, glibenclamide-sensitive K-current developed spontaneously in 5 out of 11 cells with the simultaneous reduction of IK(V). In 3 of the 6 remaining cells, addition of the dephosphorylating agent, butanedione monoxime (5 mM) to the bath inhibited IK(V) and stimulated a glibenclamide-sensitive non-inactivating current. 8. Depletion of intracellular Mg2+ slightly enhanced IK(V). Under these conditions, levcromakalim (1 microM and 10 microM) did not significantly induce IK(ATP) or inhibit IK(V). 9. It is concluded that the effects of levcromakalim on K-currents can be mimicked by procedures designed to reduce channel phosphorylation. The results are consistent with the view that levcromkalim dephosphorylates the delayed rectifier channel, KV, which becomes converted into a voltage-independent, non-inactivating form known as KATP. The possible mechanisms which underlie this interconversion are discussed.

Animals↗
PubMed1991

Effects of anesthetics and convulsants on the resting potassium conductance in squid nerve.

The effects of some fluorinated anesthetics and convulsants on the ionic conductances of the axon membrane of the squid Loligo forbesi are described. The substances studied were the inhalation anesthetics enflurane (CF2HOCF2CClFH) and isoflurane (CF2HOCClHCF3) and the convulsants flurothyl (CF3CH2OCH2CF3) and trichlorofluormethane (CCl3F). At low concentrations (0.4-0.8 mM), none of these substances significantly affected the voltage-dependent Na and K channels of the nerve. However, at these concentrations each substance produced a depolarization of the resting potential and reduced the potassium conductance of the resting membrane. This was associated with a tendency to cause axonal hyperexcitability. The potassium conductance of the resting membrane was separated into a component arising from residual open Hodgkin-Huxley delayed rectifier K channels and another voltage-independent component (g'k). The former component was insensitive to the test substances at 0.4-0.8 mM, while g'k was inhibited by 40-80%. It is suggested that the convulsant activity of certain small fluorinated molecules, and the proconvulsant actions of certain clinical anesthetics at low concentrations, may be related to the inhibition of a resting, voltage-independent potassium conductance system in the nerve membrane.

Action Potentials↗
PubMed1986

Action potentials, macroscopic and single channel currents recorded from growth cones of Aplysia neurones in culture.

Action potentials, macroscopic ionic currents and single channel currents were recorded from growth cones of Aplysia right upper quadrant (r.u.q.) cells in culture, using the patch-clamp technique. Recordings were obtained from both intact growth cones and from growth cones that had been mechanically isolated from the rest of the neurone. In current-clamp mode, greater than half of the isolated growth cones display an all-or-none action potential when depolarized above 0 mV with outward current pulses. The remaining growth cones display only a graded depolarization that is unaffected by tetrodotoxin (TTX). In whole-cell voltage clamp almost all isolated growth cones display a rapidly activating and inactivating inward current followed by a delayed outward current in response to depolarizations positive to -20 mV. The rapid inward current reverses direction at around +70 to +80 mV and is completely suppressed by 100 microM-TTX, which suggests that this current is carried by the fast Hodgkin-Huxley sodium current channels. The delayed outward current appears to result from the activation of both the delayed rectifier potassium current, IK, and the calcium-activated potassium current, IC. The growth cones do not display any prominent early transient outward current, IA. The sodium current, INA, was studied in isolation by substituting caesium for potassium ions in the pipette solution. INa is half-inactivated at a holding potential of -36 mV, reaches half-maximal activation with a depolarization to 0 mV, and has a mean peak current density of 13 microA/cm2. The time course of inactivation is well described by a single exponential (tau = 3 ms at 0 mV). In cell-attached patches, a rapidly activating and inactivating inward current channel was recorded with an average unit conductance of 6.9 pS. The activation and inactivation parameters of the ensemble averaged current closely match the measured values from the macroscopic sodium current. At very positive potentials we recorded a voltage-dependent outward current channel with a conductance of around 35 pS. No significant inward calcium current was observed in whole-cell measurements and few single calcium channel currents were measured in cell-attached patches, suggesting a sparse distribution of calcium channels in the r.u.q. growth cones.

Action Potentials↗
PubMed2002

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine.

1. The inhibition of the cardiac 'rapid' delayed rectifier current (I(Kr)) and its cloned equivalent HERG mediate QT interval prolonging effects of a wide range of clinically used drugs. In this study, we investigated the effects of the Class Ic antiarrhythmic agent flecainide (FLEC) on ionic current (I(HERG)) mediated by cloned HERG channels at 37 degrees C. We also compared the inhibitory potency of FLEC with other Class I agents: quinidine (QUIN, Class Ia); lignocaine (LIG, Class Ib) and propafenone (PROPAF, Class Ic). 2. Whole cell voltage clamp recordings of I(HERG) were made from an HEK293 cell line stably expressing HERG. FLEC inhibited I(HERG) 'tails' following test pulses to +30 mV with an IC(50) of 3.91+/-0.68 microM (mean+/-s.e.mean) and a Hill co-efficient close to 1 (0.76+/-0.09). 3. In experiments in which I(HERG) tails were monitored following voltage commands to a range of test potentials, I(HERG) inhibition by FLEC was observed to be voltage-dependent and to be associated with a approximately -5 mV shift of the activation curve for the current. Voltage-dependence of inhibition was greatest over the range of potentials corresponding to the steep portion of the I(HERG) activation curve. The time-course of I(HERG) tail deactivation was not significantly altered by FLEC. 4. In experiments in which 10 s depolarizing pulses were applied from -80 to 0 mV, the level of current inhibition by FLEC did not increase between 1 and 10 s. Some time-dependence of inhibition was observed during the first 200 - 300 ms of depolarization. This observation and the voltage-dependence of inhibition are collectively consistent with FLEC exerting a rapid open channel state inhibition of I(HERG). 5. Under similar recording conditions QUIN inhibited I(HERG) with an IC(50) of 0.41+/-0.04 microM and PROPAF inhibited I(HERG) with an IC(50) of 0.44+/-0.07 microM. Similar to FLEC, both QUIN and PROPAF showed voltage-dependence of inhibition and blockade developed rapidly during a sustained depolarization. 6. LIG showed little effect on I(HERG) at low micromolar concentrations, but could inhibit the current at higher concentrations; the observed IC(50) was 262.90+/-22.40 microM. 7. Our data are consistent with FLEC, PROPAF and QUIN exerting I(HERG) blockade at clinically relevant concentrations. The rank potency as HERG blockers of the Class I drugs tested in this study was QUIN=PROPAF>FLEC>>LIG.

Cation Transport Proteins↗
PubMed1997

Amino terminal-dependent gating of the potassium channel rat eag is compensated by a mutation in the S4 segment.

1. Rat eag potassium channels (r-eag) were expressed in Xenopus oocytes. They gave rise to delayed rectifying K+ currents with a strong Cole-Moore effect. 2. Deletions in the N-terminal structure of r-eag either shifted the activation threshold to more negative potentials and slowed the activation kinetics (delta 2-190, delta 2-12 and delta 7-12) or resulted in a shift to more positive potentials and faster activation kinetics (delta 150-162). 3. The impact of the deletion delta 7-12 was investigated in more detail: it almost abolished the Cole-Moore effect and markedly slowed down channel deactivation. 4. Unlike wild-type channels, the deletion mutants delta 7-12 exhibited a rapid inactivation which, in combination with the slow deactivation, resulted in current characteristics which were similar to those of the related potassium channel HERG. 5. Both the slowing of deactivation and the inactivation induced by the deletion delta 7-12 were compensated by a single histidine-to-arginine change in the S4 segment, while this mutation (H343R) only had minor effects on the gating kinetics of the full-length r-eag channel. 6. These results demonstrate a functional role of the N-terminus in the voltage-dependent gating of potassium channels which is presumably mediated by an interaction of the N-terminal protein structure with the S4 motif during the gating process.

Amino Acid Sequence↗
PubMed2001

Inhibition of HERG potassium channel current by the class 1a antiarrhythmic agent disopyramide.

The Class 1a antiarrhythmic drug disopyramide (DISO) is associated with 'acquired' prolongation of the QT interval of the electrocardiogram (ECG). This potentially proarrhythmic effect is likely to reflect drug actions on ion channels involved in ventricular action potential repolarisation. In this study, we examined the effects of DISO on potassium channels encoded by HERG, as this K channel type has been implicated in both congenital and acquired long-QT syndromes (LQTS). Chinese hamster ovary cells were transiently transfected with HERG cDNA for subsequent whole cell patch clamp recording. HERG tail currents recorded at -40 mV following test pulses to +30 mV were inhibited in a dose-dependent fashion by DISO concentrations within the clinical range (IC50 = 7.23 +/- 0.72 microM; mean +/- SEM). Experiments with 10 microM DISO indicated that the degree of HERG blockade showed some voltage dependence. Further data obtained using an 'envelope of tails' protocol (pulse potential +40 mV) were consistent with a significant role for open-channel blockade at lower drug concentrations. At higher concentrations it is possible that blockade may have involved drug binding to both resting and open channels. Inhibition of the inactivation-deficient mutant HERG-S631A was comparable to that seen for wild-type HERG. Therefore, channel inactivation was not obligatory for DISO to exert its effect. Native delayed rectifier tail currents from rabbit isolated ventricular myocytes were also inhibited by DISO. We conclude (a) that DISO inhibits HERG encoded potassium channels at clinically relevant concentrations and (b) that this action may constitute the molecular basis for acquired LQTS associated with this drug.

Animals↗
PubMed1999

Arrhythmogenic mechanisms of non-sedating antihistamines.

Antihistamines (H1-receptor antagonists) are amongst the most frequently prescribed drugs worldwide for the treatment of allergic conditions. Recently, there have been reports that certain non-sedating antihistamines, mainly terfenadine and astemizole, might be associated with the risk of rare but severe arrhythmias, namely torsades de pointes, particularly in overdosage, concomitant ingestion of imidazole or macrolide antibiotics and in patients with underlying cardiac or liver diseases. It has now been shown that the molecular target in human ventricle for the potassium channel blockade of antihistamine is HERG gene located in chromosome 7 that expresses the delayed rectifier IKr and appears to be involved in the congenital long QT syndrome. Mechanistic studies showed that blockade of IKr channels by these drugs leads to prolongation of the monophasic action potential (QT interval on surface electrocardiogram) which may then induce the development of early after-depolarization and dispersion of repolarisation leading to torsades de pointes through re-entry mechanism. There are still many questions that need to be answered such as the roles of other potassium channels (IKs, Ito, and Iped) and the relative expression of various potassium channels in different individuals which may be important in the pathogenesis of torsades de pointes with non-sedating antihistamines. There is also a lack of information on the cardiac actions of newer non-sedating antihistamines. It is hoped that with a better understanding of the arrhythmogenic mechanism of non-sedating antihistamines, one will be able to identify those at risk patients and prevent any cardiac toxicity associated with antihistamines and ultimately death.

Arrhythmias, Cardiac↗
PubMed2003

Pharmacological activation of normal and arrhythmia-associated mutant KCNQ1 potassium channels.

KCNQ1 alpha-subunits coassemble with KCNE1 beta-subunits to form channels that conduct the slow delayed rectifier K+ current (IKs) important for repolarization of the cardiac action potential. Mutations in KCNQ1 reduce IKs and cause long-QT syndrome, a disorder of ventricular repolarization that predisposes affected individuals to arrhythmia and sudden death. Current therapy for long-QT syndrome is inadequate. R-L3 is a benzodiazepine that activates IKs and has the potential to provide gene-specific therapy. In the present study, we characterize the molecular determinants of R-L3 interaction with KCNQ1 channels, use computer modeling to propose a mechanism for drug-induced changes in channel gating, and determine its effect on several long-QT syndrome-associated mutant KCNQ1 channels heterologously expressed in Xenopus oocytes. Scanning mutagenesis combined with voltage-clamp analysis indicated that R-L3 interacts with specific residues located in the 5th and 6th transmembrane domains of KCNQ1 subunits. Most KCNQ1 mutant channels responded to R-L3 similarly to wild-type channels, but one mutant channel (G306R) was insensitive to R-L3 possibly because it disrupted a key component of the drug-binding site.

Amino Acid Substitution↗
PubMed1994

Outwardly rectifying potassium currents in lens epithelial cell membranes.

Isolated epithelial cells from chick, pig, monkey, rabbit, bovine, and human lenses contain K+ channels that often turn on with a delay after a voltage step and have a larger macroscopic conductance for outward currents than for inward currents even with the same K+ concentration on both sides of the membrane. These outward rectifiers are quite diverse between different lens types and more than one kind can be present even within a single lens species. The channels differ substantially in the voltage dependence of their opening, their deactivation time constants, and the time course of their inactivation. Most produce currents of the delayed rectifier type but others show similarities to A-type currents. Because these different channels open at different voltages, inactivate to different degrees and represent different fractions of the total conductance from one lens cell to another, their contribution to the resting voltage is not the same in all cells investigated. These currents are the most frequently occurring in bovine, pig, monkey, and human lens epithelium and also occur commonly in chick lens epithelium. They occur less frequently in rodents.

Animals↗
PubMed1997

Effects of a cognition-enhancer, linopirdine (DuP 996), on M-type potassium currents (IK(M)) and some other voltage- and ligand-gated membrane currents in rat sympathetic neurons.

Linopirdine is a cognition enhancer which augments depolarization-induced transmitter release in the cortex and which is under consideration for potential treatment of Alzheimer's disease. It has previously been reported to inhibit M-type K+ currents in rat hippocampal neurons. In the present experiments we have tested its effect on whole-cell M-currents and single M-channels, and on a range of other membrane currents, in dissociated rat superior cervical sympathetic ganglion cells. Linopirdine inhibited the whole-cell M-current with an IC50 of 3.4 microM and blocked M-channels recorded in excised outside-out membrane patches but not in inside-out patches. This suggests that linopirdine directly blocks M-channels from the outside. It was much less effective in inhibiting other voltage-gated potassium currents [delayed rectifier (IK(V)), IC50 63 microM; transient (IA) current, IC50 69 microM] and produced no detectable inhibition of the fast and slow Ca(2+)-activated K+ currents IC and IAHP or of a hyperpolarization-activated cation current (IQ/Ih) at 10-30 microM. However, it reduced acetylcholine-activated nicotinic currents and GABA-activated Cl- currents with IC50 values of 7.6 and 26 microM respectively. It is concluded that linopirdine shows some 20-fold selectivity for M-channels among different K+ channels but can also block some transmitter-gated channels. The relationship between M-channel block and the central actions of linopirdine are discussed.

Animals↗