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Results for “Delayed Rectifier Potassium Channels”

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PubMed1998

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

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

Amino Acid Sequence↗

PubMed1999

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

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

Algorithms↗

PubMed1999

Overexpression of a human potassium channel suppresses cardiac hyperexcitability in rabbit ventricular myocytes.

The high incidence of sudden death in heart failure may reflect abnormalities of repolarization and heightened susceptibility to arrhythmogenic early afterdepolarizations (EADs). We hypothesized that overexpression of the human K+ channel HERG (human ether-a-go-go-related gene) could enhance repolarization and suppress EADs. Adult rabbit ventricular myocytes were maintained in primary culture, which suffices to prolong action potentials and predisposes to EADs. To achieve efficient gene transfer, we created AdHERG, a recombinant adenovirus containing the HERG gene driven by a Rous sarcoma virus (RSV) promoter. The virally expressed HERG current exhibited pharmacologic and kinetic properties like those of native IKr. Transient outward currents in AdHERG-infected myocytes were similar in magnitude to those in control cells, while stimulated action potentials (0.2 Hz, 37 degrees C) were abbreviated compared with controls. The occurrence of EADs during a train of action potentials was reduced by more than fourfold, and the relative refractory period was increased in AdHERG-infected myocytes compared with control cells. Gene transfer of delayed rectifier potassium channels represents a novel and effective strategy to suppress arrhythmias caused by unstable repolarization.

Action Potentials↗

PubMed1994

The novel class III antiarrhythmics NE-10064 and NE-10133 inhibit IsK channels expressed in Xenopus oocytes and IKs in guinea pig cardiac myocytes.

Slowly activating, voltage-dependent IsK channels were expressed in Xenopus oocytes after injection of rat IsK protein cRNA and recorded with the two-microelectrode voltage-clamp technique. The IsK currents were inhibited by the new class III antiarrhythmic drugs NE-10064 and NE-10133. These compounds were equally potent in inhibiting a slowly activating potassium current (IKs) in guinea pig ventricular myocytes. No effects of these compounds could be observed on several other cloned delayed rectifier potassium channels, nor did they affect the inward rectifier current, IK1, in guinea pig cardiac myocytes at the concentrations tested. The blockade of IsK channels may contribute to the class III antiarrhythmic efficacy of these novel antiarrhythmics.

Animals↗

PubMed1993

Functional significance of the A-current.

This work considers the response to simulated synaptic inputs of an excitable membrane model. The model is essentially of the Hodgkin-Huxley type, but contains an A-current in addition to sodium and delayed-rectifier potassium channels. The results were compared with previous simulations in which the stimulus was an injected current. These two types of stimuli give somewhat different results because synaptic stimuli directly change the membrane resistance, whereas injected current does not. The results of synaptic stimulation were similar to injected current in that very low frequencies of action potentials were elicited only where the stimulus was slightly above threshold. For most of the range of synaptic inputs that produced oscillatory behavior, the A-current had little effect on oscillation frequency. With synaptic stimuli as with injected current, the model membrane's spiking behavior does not begin immediately when an excitatory stimulus is imposed on a quiescent state. The delay before spiking is closely related to the inactivation time of the A-current. The synaptic results were different from the injected current results in that when substantial inhibition was present, the ability to produce very-low-frequency spiking was absent, even just above the excitatory threshold. The higher the degree of inhibition, the narrower the range of spike frequencies that could be elicited by excitation. At very high inhibition, no degree of excitation could elicit spiking.

Action Potentials↗

PubMed1990

Global parameter optimization for cardiac potassium channel gating models.

Quantitative ion channel model evaluation requires the estimation of voltage dependent rate constants. We have tested whether a unique set of rate constants can be reliably extracted from nonstationary macroscopic voltage clamp potassium current data. For many models, the rate constants derived independently at different membrane potentials are not unique. Therefore, our approach has been to use the exponential voltage dependence predicted from reaction rate theory (Stevens, C. F. 1978. Biophys. J. 22:295-306; Eyring, H., S. H. Lin, and S. M. Lin. 1980. Basic Chemical Kinetics. Wiley and Sons, New York) to couple the rate constants derived at different membrane potentials. This constrained the solution set of rate constants to only those that also obeyed this additional set of equations, which was sufficient to obtain a unique solution. We have tested this approach with data obtained from macroscopic delayed rectifier potassium channel currents in voltage-clamped guinea pig ventricular myocyte membranes. This potassium channel has relatively simple kinetics without an inactivation process and provided a convenient system to determine a globally optimized set of voltage-dependent rate constants for a Markov kinetic model. The ability of the fitting algorithm to extract rate constants from the macroscopic current data was tested using "data" synthesized from known rate constants. The simulated data sets were analyzed with the global fitting procedure and the fitted rate constants were compared with the rate constants used to generate the data. Monte Carlo methods were used to examine the accuracy of the estimated kinetic parameters. This global fitting approach provided a useful and convenient method for reliably extracting Markov rate constants from macroscopic voltage clamp data over a broad range of membrane potentials. The limitations of the method and the dependence on initial guesses are described.

Analysis of Variance↗

PubMed1999

Characterization of Ca(2+)-inhibited potassium channels in the LNCaP human prostate cancer cell line.

Potassium plasma membrane channels have been studied in the LNCaP androgen-sensitive human prostate cancer cell line, derived from a lymph node of a subject with metastatic carcinoma of the prostate. Membrane currents were recorded by the patchclamp technique, using the cell-attached, cell-free and whole-cell mode. A voltage-dependent, non-inactivating potassium channel (delayed rectifier) was the most commonly observed ion channel in LNCaP cells. The slope conductance of K+ channels in a symmetrical 140 mM K+ gradient was 78 pS. In excised inside-out patches, the channel was inhibited by increasing the cytoplasmic Ca2+ concentration (with half-block at 0.5 microM Ca2+) over a wide range of membrane potentials. The K+ channel had a high sensitivity to tetraethylammonium (TEA), that reduced the single channel conductance with Kd of 280 +/- 27 microM. The K+ channel open probability was inhibited by alpha-dendrotoxin (DTX) (with a half-blocking concentration of approximately 5 nM) and mast cell degranulating peptide (MCDP) (with half-blocking concentration of approximately 70 nM) at all membrane potentials and with very slow reversibility. In view of the biophysical and pharmacological properties of K+ channels in LNCaP cells, it is not possible to classify these channels as one of the previously characterized types of voltage- or ligand-gated K+ channels in other cell lines.

Adenocarcinoma↗

PubMed1995

Serotonin modulates the voltage dependence of delayed rectifier and Shaker potassium channels in Drosophila photoreceptors.

We describe the in situ modulation of potassium channels in a semi-intact preparation of the Drosophila retina. In whole-cell recordings of photoreceptors, rapidly inactivating Shaker channels are characterized by a conspicuously negative voltage operating range; together with a delayed rectifier, these channels are specifically modulated by the putative efferent neurotransmitter serotonin. Contrary to most potassium channel modulations, serotonin induced a reversible positive shift in the voltage operating range, of +30 mV for the Shaker channels and +10-14 mV for the delayed rectifier. The maximal current amplitudes were unaffected. Modulation was not affected by the subunit-specific Shaker mutations ShE62 and T(1;Y)W32 or a null mutation of the putative modulatory subunit eag. The modulation of both channels was mimicked by intracellularly applied GTP gamma S.

Animals↗

PubMed1998

Adenosine potentiates the delayed-rectifier potassium conductance but has no effect on the hyperpolarization-activated Ih current in frog melanotrophs.

The effects of adenosine on the voltage-sensitive delayed-rectifier K+ (IK) currents and hyperpolarization-activated cationic inward current (Ih) were studied in cultured frog melanotrophs using the whole-cell configuration of the patch-clamp technique. The A1 receptor agonist R-N6-phenylisopropyl-adenosine (R-PIA; 50 microM) reversibly increased IK. Perfusion of dibutyryl-cAMP (1 mM) in the external solution did not modify the R-PIA-induced enhancement of IK. Pretreatment of melanotrophs with pertussis toxin (1 microg/ml; 12 h) totally abolished the R-PIA-evoked response. Application of hyperpolarizing voltage pulses from -60 to -120 mV to melanotrophs induced a two-component inward current corresponding to an Ih-like conductance. This conductance was characterized by a high K+ selectivity and a low Na+ permeability and was resistant to tetrodotoxin (1 microM). R-PIA had no effect on Ih. The present study demonstrates that in frog melanotrophs adenosine inhibits the electrical activity by activating IK through an A1 receptor subtype coupled to a pertussis toxin-sensitive pathway independent of the cAMP/PKA system. This study also demonstrates the existence of a Ih conductance in frog melanotrophs which is not modulated by A1 receptors.

Adenosine↗

PubMed1999

Altered molecular architecture of peripheral nerves in mice lacking the peripheral myelin protein 22 or connexin32.

Peripheral nerves of mutant mice deficient for peripheral myelin protein 22 (PMP22) or connexin32 (Cx32) display similar pathologies as observed in hereditary human peripheral neuropathies. Mice lacking PMP22 develop focal hypermyelination followed by myelin degeneration and axonal atrophy. Cx32-deficient mice form normal myelin initially but develop demyelination and remyelination at older ages. We have examined the lack of PMP22 or Cx32 on the distribution of other components of the myelin sheath including myelin basic protein (MBP), E-cadherin, and myelin-associated glycoprotein (MAG), as well as the delayed rectifying potassium channel Kv1.1 as an intrinsic membrane protein of axons. In peripheral nerves of wild-type mice, Kv1.1 is present as a pair of juxtaparanodal clusters and a focal line extending longitudinally into the internode, branching parallel and adjacent to Schmidt-Lanterman incisures. Myelinated peripheral nerve fibers of 3-week-old PMP22(0/0) mice show tomacula and abnormally short internodes of variable lengths with minor effects on the localization of E-cadherin and Kv1.1. In older PMP22(0/0) mice, hypomyelinated fibers contain supernumerary Schwann cells and loose focally restricted E-cadherin and Kv1.1 expression. In contrast, remyelinated fibers in adult Cx32(0/0) mice exhibit a correct localization of these marker proteins, except that juxtaparanodal Kv1.1 clusters are aligned in abnormally short intervals of regular distances accompanied by an increased number of Schwann cells. Thus, different degrees of demyelination and remyelination in demyelinating mouse models have variable effects on the confinement of specific proteins to structural and functional internodal domains.

Animals↗

PubMedDate not supplied

Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factor.

The present view of the neuroprotective functions and mechanisms of action of vascular endothelial growth factor (VEGF) is based on studies of neuronal ischemic/hypoxic models in vivo and in vitro. Endogenous neuronal VEGF increases in the ischemic brain and plays a neuroprotective role in the pathophysiologic processes that follow stroke. Exogenous VEGF, directly administered or overexpressed by gene delivery into rat brains, reduces ischemic brain infarct and decreases hypoxic neuronal death. The main neuroprotective mechanisms of VEGF include: (1) modulation of the phosphatidylinositol 3'-kinase (PI3K)/Akt/nuclear factor-kappaB signaling pathway, inhibition of caspase-3 activity, and reduction of ischemic neuronal apoptosis; (2) inhibition of outward delayed rectifier potassium channel currents and increase of ischemia-induced tyrosine phosphorylation of Kv1.2 potassium channel proteins via activation of the PI3K pathway; and (3) enhancement of proliferation and migration of neural progenitors in the subventricular zone and improvement of striatal neurogenesis and maturation of newborn neurons in adult rat brains after stroke.

Animals↗

PubMed1997

[3H]dofetilide binding to cardiac myocytes: modulation by extracellular potassium.

UNLABELLED: The radioligand [3H]dofetilide binds specifically to the delayed rectifier potassium channel and provides a biochemical approach to study interactions of Class III drugs with this channel. However, previous studies have examined the binding of [3H]dofetilide to cardiac myocytes only at extracellular potassium of 135 mM. Because previous electrophysiological studies have shown that hyperkalemia could alter the pharmacological responses to I(Kr) channel blockers, the hypothesis tested in this study was that changing ionic conditions would alter characteristics of [3H]dofetilide binding. RESULTS: under physiological conditions (Na+ 135 mM, K+ 5 mM), [3H]dofetilide bound to two sites on guinea-pig ventricular myocytes (a high-affinity site, K(d) 26+/-8 nM, B(max) 81+/-12 fmol/10(6) cells: and a low-affinity site, K(d) 1.6+/-0.8 microM, B(max) 1003+/-173 fmol/10(6) cells, n=11). Binding properties were not altered by changes in osmolarity or extracellular sodium. However, when extracellular K+ was increased to 20 mM, a single binding site was observed with an affinity K(d) of 120+12 nM and a B(max) of 303+/-57 fmol/10(6) cells (P<0.05; n=6). To establish whether this effect was mediated at the high-affinity site we assessed the effects of elevated extracellular potassium on a biological model, neonatal mouse myocytes, that expressed solely the high-affinity binding sites. The K(d) values for binding to fetal mouse cardiac myocytes at an extracellular K+ of 5 mM and 20 mM were also significantly different, 29+/-10 and 230+/-46 nM, respectively. In conclusion, [3H]dofetilide binding to its high-affinity site is modulated by extracellular potassium.

Animals↗

PubMed2001

Characterization and subcellular localization of KCNQ1 with a heterozygous mutation in the C terminus.

Numerous mutations in KCNQ1, a gene encoding the alpha -subunit of cardiac delayed rectifier potassium channels, have been found in long QT syndrome (LQTS). Among them, several mutations in the C terminus have been shown to cause autosomal recessive or subclinical autosomal dominant LQTS. Here, we report a heterozygous mutation, T587M, which is also in the KCNQ1 C-terminal domain. The same mutation was found in three independent probands that were clearly symptomatic with family history of cardiac sudden death. Functional assay using a heterologous expression system with a mammalian cell line (COS7 cells) revealed that the mutant displayed neither functional channels when expressed alone nor dominant-negative effect when co-expressed with wild-type (WT) KCNQ1. To examine the cellular trafficking of KCNQ1, green fluorescent protein (GFP) was tagged to the cytoplasmic C terminus of WT or mutant KCNQ1. This procedure did not affect the essential properties of expressed WT KCNQ1 channels. On confocal microscopic images, GFP-tagged WT KCNQ1 showed a plasma membrane fluorescence pattern, whereas the GFP-tagged mutant showed a perinuclear fluorescence pattern. Co-expression of the mutant with GFP-tagged WT KCNQ1 did not influence its normal cellular transport. Therefore, the T587M mutant cannot traffic to the plasma membrane and may form no subunit assembly with WT KCNQ1. These findings provide a novel molecular basis for the clinical finding that this C-terminal mutation produced a severe form of RWS-type LQTS.

Adolescent↗

PubMed2000

Pharmacokinetic data support pharmacologically induced embryonic dysrhythmia as explanation to Fetal Hydantoin Syndrome in rats.

New studies suggest that the teratogenicity of phenytoin (PHT) is linked to its membrane-stabilizing pharmacological action via the rapid component of the delayed rectified potassium channel (lkr), resulting in embryonic cardiac dysrhythmia during a restricted sensitive period. In order to further elucidate this theory, PHT was administered to Sprague-Dawley rats on gestation day (GD) 11 with either a single dose of 150 or 100 mg/kg ip or 150 mg/kg po and developmental toxicity at term (GD 21) was studied. In satellite animals blood samples were withdrawn (0.5-24 h after dose) and total and free maternal plasma concentrations of PHT were measured. Pharmacokinetic data correlated well with pregnancy outcome data. At 150 mg/kg ip high concentrations of long duration (C(max) 240 microM and AUC 5300 microMhl(-1) - total) and marked developmental toxicity (embryonic death, decreased fetal weights, and orofacial clefts) were observed. After 100 mg/kg ip (C(max) 150 microM, AUC 2600 microMhl(-1) - total) only slight developmental toxicity (decreased fetal weights) was recorded and after 150 mg/kg po the plasma concentrations were even lower (C(max) 63 microM and AUC 1100 microMhl(-1) - total) and no adverse effects at all were observed. In separate experiments the effect of different concentrations of PHT on the embryonic heart was studied by adding PHT to GD 11 rat embryos cultured in vitro or by culturing GD 11 embryos from exposed dams. The decrease in heart rates was 3, 16, and 32% after culture with 50, 100, and 200 microM of PHT, respectively. After maternal administration of 150 mg/kg ip or po, the embryonic heart rate in vitro decreased by 25 and 7%, respectively, compared to controls. Altogether the results suggest that the development toxicity of PHT is caused by concentration-dependent induction of embryonic dysrhythmia and hypoxia related damage.

Abnormalities, Drug-Induced↗

PubMed1998

The heart rate-corrected QT interval of conscious beagle dogs: a formula based on analysis of covariance.

Three frequently used and cited formulas used to rate correct the QT interval (Bazett's, Fridericia's, and Van de Water's) were compared and ranked using a large population-based cohort of beagle dogs (99 males and 99 females). In addition, analysis of covariance was used to derive a flexible method to rate correct the QT.interval for heart rate. The method is flexible in that it utilizes pretest or control data to determine the degree of correction. In addition, it can also be used to evaluate whether treatment alters the association between heart rate and QT. Specifically, pretest QT (unadjusted) and heart rate data were used to estimate coefficients in the linear regression log(QT) = alpha + beta log(HR). The estimated slope (beta) from the pretest data was used to heart rate correct the QT interval in the formula log(QT)ca = log(QT) - beta *[log(HR - log(HRm)]. The term "log(HRm)" is included to standardize QTca to a reference value, either a fixed value or an average heart rate for the data set being analyzed. These formulas were retrospectively compared under a typical toxicity study paradigm with a class III antiarrhythmic agent (L-768,673) that selectively prolongs the QT interval by blocking the slow activating component of the delayed rectifying potassium channel (lks). Based on their ability to dissociate the effects of heart rate on the QT interval, the formulas received the following ranking: Covariate Adjustment (preferred) = Van De Water's > Fridericia's > Bazett's (not recommended). Analysis of covariance based on pretest or control data is preferred for moderate to large studies where there are adequate data for estimation of the slope parameter beta, the investigator does not have sufficient control over HR, or treatment alters the association between HR and the QT interval. Conversely, for smaller studies a fixed rate adjustment formula from the literature (such as Van de Water's or Fridericia's equations) may be preferable since the bias from using a fixed formula is likely to be smaller than the variance resulting from estimating beta from a small sample.

Acetamides↗

PubMed2002

Temperature dependence of bistability in squid giant axons with alkaline intracellular pH.

Raising the intracellular pH (pHi) above 7.7 in intracellularly perfused squid giant axons causes spontaneous firing of action potentials. The firing frequency ranged from 20 Hz at 0 degrees C to 200 Hz at 23 degrees C. Above 23 degrees C, the axons were quiescent. They were bistable for 13 <T <23 degrees C. That is, they were either quiescent or spontaneously firing. Below 13 degrees C, spontaneous firing was the only stable element. The primary effects of changes in temperature on the underlying ionic currents were on gating of the delayed rectifier potassium channel IK, and the sodium ion channel INa. The kinetics of IK had a Q10 of 3.63. The effect of T on INa was more complicated in that the peak INa amplitude increased with T, as demonstrated in earlier reports. This effect, as well as the changes in INa kinetics produced by changes in T, were mimicked in the context of a model of INa gating in which activation and inactivations are coupled. Electrical activity was simulated in a model of the action potential with appropriate temperature-dependent modifications for INa and IK. The model predicts a change from monostability (spontaneous firing) at relatively low temperatures to bistability (quiescence and spontaneous firing) as the temperature is raised, followed by change back to monostability (quiescence) as the temperature is further increased, which is consistent with the experimental results.

Action Potentials↗

PubMed1998

Effects of ruthenium red on membrane ionic currents in urinary bladder smooth muscle cells of the guinea-pig.

Three major ionic currents, Ca2+-dependent K+ current (IK-Ca), delayed rectifier type K+ current (Ikd) and Ca2+ current (ICa), were activated by depolarization under whole-cell clamp in single smooth muscle cells isolated from guinea-pig urinary bladder. Externally applied ruthenium red (RuR) reduced the amplitude of IK-Ca and ICa at 0 mV (IC50 values were 4.2 and 5.6 muM, respectively), but did not affect IKd. Spontaneous transient outward currents (STOCs) and caffeine-induced outward currents (Icaf) at -30 mV were reduced by external 10 muM RuR. When 10 muM RuR was added to the pipette solution, IK-Ca during depolarization, STOCs and Icaf significantly decreased with time. RuR did not change the unitary current amplitude of the large-conductance Ca2+-dependent K+ (BK) channels, but reduced the open probability of the channel under excised patch-clamp recording mode. RuR reduced the channel activity more effectively from the cytosolic face than from the other. This inhibition decreased when the cytosolic Ca2+ concentration was increased. These results indicate that RuR blocks BK and Ca2+ channels in urinary bladder smooth muscle cells. The decrease in IK-Ca, STOCs and Icaf by RuR is attributable to the direct inhibition of BK channel activity, probably in addition to the inhibition of Ca2+ release from storage sites. The direct inhibition of BK channel activity by RuR may be related to the interaction of RuR with the Ca2+-binding sites of the channel protein.

Animals↗

PubMed1999

Maturation and myotonia influence the abundance of cation channels KDR, KIR and CIR differently: a patch-clamp study on mouse interosseus muscle fibres.

To detect cation channels, the expression of which is dependent on the physiological state of muscle, single-channel activities of dissociated fibres of the mouse interosseus muscle were recorded using the patch-clamp technique in the cell-attached mode. Fibres were prepared from juvenile and adult wild-type (WT), from chloride channel-deficient myotonic and from denervated adult WT muscles. In all cases delayed-rectifier K+ channels (KDR) with a unitary conductance of 11 pS were recorded in more than 95% of sarcolemmal patches, but with a low, steady-state open probability. Inwards-rectifying K+ channels (KIR) with a conductance of 31 pS in 140 mM [K+]o were active in about 50% of the membrane patches from WT and in more than 90% of those from myotonic fibres. A hitherto undescribed, inwards-rectifying, cation channel, provisionally termed CIR, with fast kinetics and a unitary conductance of 36 pS, was active in nearly every membrane patch from juvenile mice, both WT and myotonic. The abundance of CIR decreased during development, but was not changed 7 days after denervation of adult WT muscle. Ca(2+)-dependent K+ channels were seen sporadically. Channels with the characteristics of adenosine 5'-triphosphate (ATP)-sensitive K+ channels were recorded frequently upon excision of membrane patches, but remained inactive in most cell-attached recordings. In conclusion, of the investigated ion channels, only KIR was responsive to the activity pattern of adult muscle, whereas CIR was down-regulated during muscle maturation.

Aging↗