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PubMed1997

4-aminopyridine activates potassium currents by activation of a muscarinic receptor in feline atrial myocytes.

1. The effects of 4-aminopyridine (4-AP) on action potentials, macroscopic membrane currents and single-channel recording from cardiac left atrial myocytes of the adult cat were studied using the whole-cell and cell-attached configurations of the patch-clamp technique. 2. 4-AP (1 mM) produced a hyperpolarization of the resting membrane potential and a shortening of action potential duration. Under voltage-clamp conditions, we have found that 4-AP increased a background current and a delayed rectifier outward current. These effects were antagonized by atropine. In addition, both effects seemed to be mediated through a pertussis toxin-sensitive G protein. 3. The background current induced by 4-AP displayed properties that are highly similar to those of the inwardly rectifying potassium current activated by acetylcholine (IK(ACh)). The time-dependent potassium current activated by 4-AP has kinetic and pharmacological properties different from those of the delayed rectifier potassium current previously identified in cardiac myocytes. 4. The activation of the delayed rectifier-like potassium current could be explained by the activation of a novel muscarinic receptor subtype in which acetylcholine acts as the antagonist. Another possibility is that 4-AP activates IK(ACh) in a time- and voltage-dependent manner.

4-Aminopyridine↗
PubMed2004

In silico study of action potential and QT interval shortening due to loss of inactivation of the cardiac rapid delayed rectifier potassium current.

The rapid delayed rectifier K(+) current, I(Kr), plays a key role in repolarisation of cardiac ventricular action potentials (APs). In recent years, a novel clinical condition denoted the short QT syndrome (SQTS) has been identified and, very recently, gain in function mutations in the gene encoding the pore-forming sub-unit of the I(Kr) channel have been proposed to underlie SQTS in some patients. Here, computer simulations were used to investigate the effects of the selective loss of voltage-dependent inactivation of I(Kr) upon ventricular APs and on the QT interval of the electrocardiogram. I(Kr) and inactivation-deficient I(Kr) were incorporated into Luo-Rudy ventricular AP models. Inactivation-deficient I(Kr) produced AP shortening that was heterogeneous between endocardial, mid-myocardial, and epicardial ventricular cell models, irrespective of whether heterogeneity between these sub-regions was incorporated of slow delayed rectifier K(+) current (I(Ks)) alone, or of I(Ks) together with that of transient outward K(+) current. The selective loss of rectification of I(Kr) did not augment transmural dispersion of AP repolarisation, as AP shortening was greater in mid-myocardial than in endo- or epicardial cell models. Simulated conduction through a 1 D transmural ventricular strand was altered by incorporation of inactivation-deficient I(Kr) and the reconstructed QT interval was shortened. Collectively, these results substantiate the notion that selective loss of I(Kr) inactivation produces a gain in I(Kr) function that causes QT interval shortening.

Action Potentials↗
PubMed1999

Modulation of HERG potassium channels by extracellular magnesium and quinidine.

Torsades de pointes is a polymorphic ventricular arrhythmia resulting from congenital or drug-induced (acquired) QT prolongation. Pharmacologic suppression of repolarizing potassium currents is one mechanism causing the acquired long QT (LQT) syndrome. Recent studies have linked mutations in a gene encoding a potassium channel subunit (HERG) to the LQT syndrome. Clinical experience indicates that intravenous magnesium sulfate is effective in reversing torsades de pointes, but the molecular basis of this effect is not understood. This study was designed to investigate the effects of extracellular magnesium (Mg2+) on HERG potassium currents. HERG potassium channels were expressed in Xenopus oocytes and in a human cell line and were examined by voltage-clamp methods. Extracellular Mg2+ (0.3-10 mM) caused a concentration-dependent shift in the membrane-potential dependence of HERG channel opening, causing a reduction in K+ current. This effect was much greater than that observed in another human delayed rectifier K+ channel, hKv1.5, suggesting a specific interaction with the HERG channel. Quinidine is an antiarrhythmic drug that also causes torsades de pointes under certain conditions. Quinidine (3 microM) inhibited HERG currents expressed in oocytes by 32.1 +/- 3.2% (n = 5), whereas 1 microM quinidine inhibited HERG currents in tsA201 cells by 75.8 +/- 2.4% (n = 12). Increasing extracellular Mg2+ did not relieve the inhibition by quinidine, but caused additional suppression. These results indicate that extracellular Mg2+ exerts a direct action on HERG potassium channels, resulting in suppression of outward repolarizing potassium current. It is concluded that modulation of this important K+ current is not the mechanism by which intravenous magnesium terminates drug-induced LQT and torsades de pointes. Potent suppression of HERG channel current by quinidine, compared with that of I(Ks) and I(Na), is a likely contributor to torsades de pointes arrhythmias.

Animals↗
PubMed2003

Molecular basis of species-specific expression of repolarizing K+ currents in the heart.

There are important species-specific differences in K+ current profiles and arrhythmia susceptibility, but interspecies comparisons of K+ channel subunit expression are lacking. We quantified voltage-gated K+ channel (Kv) subunit mRNA and protein in rabbits, guinea pigs, and humans. Kv1.4, Kv4.2, and Kv4.3 mRNA was present in rabbits but undetectable in guinea pigs. MinK mRNA concentration in guinea pigs was almost threefold greater versus humans and 20-fold versus rabbits. MinK protein expression in guinea pigs was almost twofold that in humans and sixfold that in rabbits. KvLQT1 mRNA concentration was greatest in humans, and protein expression in humans was increased by approximately 2- and approximately 7-fold compared with values in rabbits and guinea pigs, respectively. The ether-a-go-go-related gene (ERG1) mRNA was more concentrated in humans, but ERG1 protein expression could not be compared across species because of epitope sequence differences. We conclude that important interspecies differences in cardiac K+ channel subunit expression exist and may contribute to the following: 1) lack of a transient outward current in the guinea pig (alpha-subunit transcription absent in the guinea pig heart); 2) small slow delayed rectifier current and torsades de pointes susceptibility in the rabbit (low-level minK expression); and 3) large slow component of the delayed rectifier current in the guinea pig (strong minK expression).

Animals↗
PubMed2002

The anti-malarial drug halofantrine and its metabolite N-desbutylhalofantrine block HERG potassium channels.

OBJECTIVE: The antimalarial drug halofantrine has been associated with QT interval prolongation and with fatal and nonfatal arrhythmias in patients without known underlying cardiac abnormalities. A common target for QT interval-prolonging drugs is the human ether-a-go-go gene (HERG) which encodes the pore forming subunit of the rapidly activating delayed rectifier K(+) current (I(Kr)). METHODS: We studied the effects of halofantrine (0.1-1000 nM) and its major metabolite N-desbutylhalofantrine (3-1000 nM) on wild type HERG K(+) channels stably expressed in HEK 293 cells, using the whole cell patch-clamp recording technique. RESULTS: Halofantrine and N-desbutylhalofantrine blocked HERG K(+) channels in a concentration-dependent manner with a half-maximal inhibitory concentration of 21.6 nM (n=31 cells) and 71.7 nM (n=18 cells), respectively. The development of drug block for both halofantrine and N-desbutylhalofantrine required channel activation indicative of open and/or inactivated state block. Drug washout or cell hyperpolarization resulted in minimal current recovery consistent with virtually irreversible binding. Using a ventricular action potential voltage clamp protocol, halofantrine and N-desbutylhalofantrine block of HERG current was greatest during phases 2 and 3 of the action potential waveform. CONCLUSION: We conclude that both halofantrine and N-desbutylhalofantrine cause high affinity block of HERG K(+) channels. Although N-desbutylhalofantrine has been suggested to be a safer antimalarial agent compared to halofantrine, our results suggest that the gain in the safety margin for QT interval prolongation-related cardiotoxicity is minimal.

Action Potentials↗
PubMed2001

Evidence for a single nucleotide polymorphism in the KCNQ1 potassium channel that underlies susceptibility to life-threatening arrhythmias.

INTRODUCTION: Congenital long QT syndrome (LQTS) is a genetically heterogeneous arrhythmogenic disorder caused by mutations in at least five different genes encoding cardiac ion channels. It was suggested recently that common polymorphisms of LQTS-associated genes might modify arrhythmia susceptibility in potential gene carriers. METHODS AND RESULTS: We examined the known LQTS genes in 95 patients with definitive or suspected LQTS. Exon-specific polymerase chain reaction single-strand conformation polymorphism and direct sequence analyses identified six patients who carried only a single nucleotide polymorphism in KCNQ1 that is found in approximately 11% of the Japanese population. This 1727G>A substitution that changes the sense of its coding sequence from glycine to serine at position 643 (G643S) was mostly associated with a milder phenotype, often precipitated by hypokalemia and bradyarrhythmias. When heterologously examined by voltage-clamp experiments, the in vitro cellular phenotype caused by the single nucleotide polymorphism revealed that G643S-KCNQ1 forms functional homomultimeric channels, producing a significantly smaller current than that of the wild-type (WT) channels. Coexpression of WT-KCNQ1 and G643S-KCNQ1 with KCNE1 resulted in approximately 30% reduction in the slow delayed rectifier K+ current I(Ks) without much alteration in the kinetic properties except its deactivation process, suggesting that the G643S substitution had a weaker dominant-negative effect on the heteromultimeric channel complexes. CONCLUSION: We demonstrate that a common polymorphism in the KCNQ1 potassium channel could be a molecular basis for mild I(Ks) dysfunction that, in the presence of appropriate precipitating factors, might predispose potential gene carriers to life-threatening arrhythmias in a specific population.

Adult↗
PubMed1988

A whole-cell and single-channel study of the voltage-dependent outward potassium current in avian hepatocytes.

Voltage-dependent membrane currents were studied in dissociated hepatocytes from chick, using the patch-clamp technique. All cells had voltage-dependent outward K+ currents; in 10% of the cells, a fast, transient, tetrodotoxin-sensitive Na+ current was identified. None of the cells had voltage-dependent inward Ca2+ currents. The K+ current activated at a membrane potential of about -10 mV, had a sigmoidal time course, and did not inactivate in 500 ms. The maximum outward conductance was 6.6 +/- 2.4 nS in 18 cells. The reversal potential, estimated from tail current measurements, shifted by 50 mV per 10-fold increase in the external K+ concentration. The current traces were fitted by n2 kinetics with voltage-dependent time constants. Omitting Ca2+ from the external bath or buffering the internal Ca2+ with EGTA did not alter the outward current, which shows that Ca2+-activated K+ currents were not present. 1-5 mM 4-aminopyridine, 0.5-2 mM BaCl2, and 0.1-1 mM CdCl2 reversibly inhibited the current. The block caused by Ba was voltage dependent. Single-channel currents were recorded in cell-attached and outside-out patches. The mean unitary conductance was 7 pS, and the channels displayed bursting kinetics. Thus, avian hepatocytes have a single type of K+ channel belonging to the delayed rectifier class of K+ channels.

4-Aminopyridine↗
PubMed1991

Electrophysiological characterization of a new member of the RCK family of rat brain K+ channels.

A novel member of the RCK family of rat brain K+ channels, called RCK2, has been sequenced and expressed in Xenopus oocytes. The K+ currents were voltage-dependent, activated within 20 ms (at 0 mV), did not inactivate in 5 s, and had a single channel conductance in frog Ringers of 8.2 pS. Compared to other members of the RCK family the pharmacological profile of RCK2 was unique in that the channel was resistant to block (IC50 = 3.3 microM) by charybdotoxin [(1988) Proc. Natl. Acad. Sci. USA 85, 3329-3333] but relatively sensitive to 4-aminopyridine (0.3 mM), tetraethylammonium (1.7 mM), alpha-dendrotoxin (25 nM), noxiustoxin (200 nM), and mast cell degranulating peptide (200 nM). Thus, RCK2 is a non-inactivating delayed rectifier K+ channel with interesting pharmacological properties.

Amino Acid Sequence↗
PubMed1991

Immunological identification and characterization of a delayed rectifier K+ channel polypeptide in rat brain.

Antibodies specific for the drk1 polypeptide were used to characterize the corresponding protein in rat brain. Recombinant and synthetic immunogens containing fragments of the drk1 polypeptide were produced. Antibodies raised to these immunogens display monospecific reactions with the same 130-kDa polypeptide on immunoblots of adult rat brain membranes. Immunoprecipitation of 125I-labeled brain membranes identifies a 38-kDa peptide in tight association with the drk1 polypeptide. Immunohistochemical staining of sections of adult rat cortex shows that drk1 protein is restricted to neurons, where staining is present on dendrites and cell bodies but not on axons. These studies point to the value of such immunological reagents to the further characterization of the components of this delayed rectifier K+ channel in the mammalian central nervous system.

Animals↗
PubMed2002

Assembly with the Kvbeta1.3 subunit modulates drug block of hKv1.5 channels.

The assembly of voltage-gated potassium (Kv) channels with beta subunits modifies the electrophysiological characteristics of the alpha subunits. Kvbeta1.3 subunits shift the midpoint of the activation curve toward more negative voltages and slow the deactivation process. In addition, the Kvbeta1.3 subunit converts hKv1.5 from a delayed rectifier with a modest degree of slow inactivation to a channel with both fast and slow components of inactivation. In the present study, we have analyzed the effects of bupivacaine and a permanently charged analog [R(+)-N-methyl-bupivacaine (RB(+)1C)] on Kvalpha1.5 and Kvalpha1.5+Kvbeta1.3 channels expressed in human embryonic kidney 293 cells using the whole-cell configuration of the patch-clamp technique. Block induced by RB(+)1C binding to its external receptor site was not modified by the presence of this beta subunit. However, hKvalpha1.5+Kvbeta1.3 channels were ~4-fold less sensitive to bupivacaine than hKv1.5 channels in the absence of beta subunits (IC(50) = 47.5 +/- 5.1 versus 13.1 +/- 0.8 microM, respectively, p < 0.01). Quinidine was also less potent to block Kvalpha1.5+Kvbeta1.3 channels than Kvalpha1.5 channels (IC(50) = 49.6 microM versus 6.2 microM, respectively). These results suggest that the Kvbeta1.3 subunit does not modify the affinity of the charged bupivacaine for its external receptor site but markedly reduces the affinity of bupivacaine and quinidine for their internal receptor site in hKv1.5 channels.

Anesthetics, Local↗
PubMed2003

Role of hyperpolarization-activated currents for the intrinsic dynamics of isolated retinal neurons.

The intrinsic dynamics of bipolar cells and rod photoreceptors isolated from tiger salamanders were studied by a patch-clamp technique combined with estimation of effective impulse responses across a range of mean membrane voltages. An increase in external K(+) reduces the gain and speeds the response in bipolar cells near and below resting potential. High external K(+) enhances the inward rectification of membrane potential, an effect mediated by a fast, hyperpolarization-activated, inwardly rectifying potassium current (K(IR)). External Cs(+) suppresses the inward-rectifying effect of external K(+). The reversal potential of the current, estimated by a novel method from a family of impulse responses below resting potential, indicates a channel that is permeable predominantly to K(+). Its permeability to Na(+), estimated from Goldman-Hodgkin-Katz voltage equation, was negligible. Whereas the activation of the delayed-rectifier K(+) current causes bandpass behavior (i.e., undershoots in the impulse responses) in bipolar cells, activation of the K(IR) current does not. In contrast, a slow hyperpolarization-activated current (I(h)) in rod photoreceptors leads to pronounced, slow undershoots near resting potential. Differences in the kinetics and ion selectivity of hyperpolarization-activated currents in bipolar cells (K(IR)) and in rod photoreceptors (I(h)) confer different dynamical behavior onto the two types of neurons.

Animals↗
PubMed1999

[Bartter's syndromes].

Bartter syndromes are defined as a family of inherited recessive autosomal tubulopathies. They are characterized by hypochloremia, hypokalemia, metabolic alkalosis associated with potassium renal leakage and normal blood pressure despite increased plasma renin activity. Three forms of the disease are identified as followed: 1) Gitelman syndrome or hypocalciuria hypomagnesemia syndrome is a mild form often discovered in childhood or teenagers in reason of tetany. It is an homogeneous disorder related to mutations of the genes encoding the thiazide-sensitive Na-Cl cotransporter located in the distal convoluted tubule. 2) Antenatal Bartter syndrome with hypercalciuria and nephrocalcinosis or hyperprostaglandin E syndrome is a severe form, often revealed by hydramnios, prematurity and growth delay. It is related to mutations of two types of genes encoding for transporters of Henle's loop: the bumetanide-sensitive cotransporter Na-K-2Cl (NKCC2) [type I] or the inwardly-rectifying potassium channel (ROMK) [type II]. 3) the classical form or type III Bartter syndrome, often revealed by dehydration in the first year of life, is associated with hypomagnesemia in 20% of cases and normal or increased calciuria. This form is related to mutations of CLCNKB gene encoding for a chloride channel in Henle's loop. This classification, in part related to the demonstration of mutations in the genes encoding for tubular chloride or potassium channels, does not fit all cases, overlapping syndromes are frequent. Moreover some endocrinological (diabetes) and neurological (deafness) abnormalities are sometimes associated with Bartter syndromes. Both phenotypic and genetic approach must help to the diagnosis of these tubulopathies.

Bartter Syndrome↗
PubMed2002

[Outwardly rectifying potassium currents in isolated outer hair cells in cochlea of guinea pig].

OBJECTIVE: The purpose of this study was to investigate electrophysiological properties of isolated outer hair cells (OHCs) from cochlea of the guinea pig, record outwardly rectifying potassium currents in OHCs with different length, analyze component of outwardly rectifying potassium currents, study kinetics of the currents. METHOD: The whole cell patch-clamp technique was used. RESULT: Whole-cell capacitance of the OHC was (30.96 +/- 2.79) pF(n = 29), zero current potential was (30 +/- 2.1) mV(n = 16) and reversal potential was (-51.67 +/- 1.84) mV(n = 9). Variation in expression of outwardly rectifying potassium currents was found in OHCs with different length, namely, potassium conductance was greater in short OHC than in tall OHC. The maximal amplitude of outwardly rectifying potassium currents were reduced by 60% in the presence of 100 mumol/L CdCl2 and change the kinetics of the currents, effects of CdCl2 on the peak currents were greater when compared to the effects on the steady-state currents (P < 0.01, n = 5). 1 mmol/L 4-aminopyridine (4-AP) inhibited 43% of the maximal amplitude of the currents and had no effect on the kinetics of the currents. Activation of the currents was described by Boltzmann equation, V1/2 = (-11.07 +/- 0.26) mV, S = (6.62 +/- 1.74) mV(n = 13). CONCLUSION: Outwardly rectifying potassium currents were composed of calcium-activated potassium current, outward delayed rectifier potassium current and A type current.

Animals↗
PubMed2003

Tight coupling of rubidium conductance and inactivation in human KCNQ1 potassium channels.

KCNQ1 K+ channels in humans are important for repolarization of cardiac action potentials and for K+ secretion in the inner ear. The pore-forming channel subunits form heteromeric complexes with small regulatory subunits of the KCNE family, in particular with KCNE1 to form channels that conduct a slow delayed rectifier K+ current, IKs. This association leads to alteration of biophysical properties, including a slowing of activation, a suppression of inactivation and an increase of the apparent single-channel conductance. In addition, inward Rb+ currents conducted by homomeric KCNQ1 channels are about threefold larger than K+ currents, whereas heteromeric KCNQ1-KCNE1 channels have smaller inward Rb+ currents compared to K+ currents. We determined inactivation properties and compared K+ vs. Rb+ inward currents for channels formed by co-assembly of KCNQ1 with KCNE1, KCNE3 and KCNE5, and for homomeric KCNQ1 channels with point mutations in the pore helix S5 or S6 transmembrane domains. Several of the channels with point mutations eliminated the apparent inactivation of KCNQ1, as described previously (Seebohm et al. 2001). We found that the extent of inactivation and the ratio of Rb+/K+ currents were positively correlated. Since the effect of Rb+ on the current size has been shown previously to be related to a fast 'flickery' process, our results suggest that inactivation of KCNQ1 channels is related to a fast flicker of the open channel. A kinetic model incorporating two open states, no explicit inactivated state and a fast flicker that is different for the two open states is able to account for the apparent inactivation and the correlation of inactivation and large Rb+ currents. We conclude that an association between KCNQ1 and KCNE subunits or removal of inactivation by mutation of KCNQ1 stabilizes the open conformation of the pore principally by altering an interaction between the pore helix and the selectivity filter and with S5/S6 domains.

Action Potentials↗
PubMed2003

The sodium-activated potassium channel is encoded by a member of the Slo gene family.

Na(+)-activated potassium channels (K(Na)) have been identified in cardiomyocytes and neurons where they may provide protection against ischemia. We now report that K(Na) is encoded by the rSlo2 gene (also called Slack), the mammalian ortholog of slo-2 in C. elegans. rSlo2, heterologously expressed, shares many properties of native K(Na) including activation by intracellular Na(+), high conductance, and prominent subconductance states. In addition to activation by Na(+), we report that rSLO-2 channels are cooperatively activated by intracellular Cl(-), similar to C. elegans SLO-2 channels. Since intracellular Na(+) and Cl(-) both rise in oxygen-deprived cells, coactivation may more effectively trigger the activity of rSLO-2 channels in ischemia. In C. elegans, mutational and physiological analysis revealed that the SLO-2 current is a major component of the delayed rectifier. We demonstrate in C. elegans that slo-2 mutants are hypersensitive to hypoxia, suggesting a conserved role for the slo-2 gene subfamily.

Amino Acid Sequence↗
PubMed1990

Potassium channels and the repolarization of cardiac cells.

What is the contribution of a particular potassium current to the repolarization of cardiac myocytes? The traditional answer to this question requires clamping the cells with step voltages, finding models that describe how individual currents depend on voltage and time, driving these models with action potentials to calculate the action currents, and evaluating the contribution of each pathway to repolarization from the action currents. Another method is to measure the action currents directly from beating cells. We isolated potassium channels in cell-attached patches and averaged the current over many beats. The average channel current, mean value of i(t), is a miniature version of the action current through corresponding channels in the membrane outside the patch. The time integral of this current, scaled by channel density, N, and membrane capacity, C, is the contribution of that particular pathway to the action potential: Vi(t) = -Ni integral of to mean value of i(u) du/C Using this procedure, we have found that the delayed rectifier, IK, turns on virtually without delay following the upstroke of the action potential and gradually declines during the plateau and repolarization phases, having nearly the shape of the action potential itself. The inward rectifier, IKl, may conduct little current during the plateau and is under the control of internal Ca. The traditional method of measuring action currents from step voltage-clamp records gives qualitatively similar results. Differences may arise because factors other than voltage modulate potassium currents in beating cells.

Animals↗
PubMed2002

Functional and pharmacological properties of canine ERG potassium channels.

We established HEK-293 cell lines that stably express functional canine ether-à-go-go-related gene (cERG) K(+) channels and examined their biophysical and pharmacological properties with whole cell patch clamp and (35)S-labeled MK-499 ([(35)S]MK-499) binding displacement. Functionally, cERG current had the hallmarks of cardiac delayed rectifier K(+) current (I(Kr)). Channel opening was time- and voltage dependent with threshold near -40 mV. The half-maximum activation voltage was -7.8 +/- 2.4 mV at 23 degrees C, shifting to -31.9 +/- 1.2 mV at 36 degrees C. Channels activated with a time constant of 13 +/- 1 ms at +20 mV, showed prominent inward rectification at depolarized potentials, were highly K(+) selective (Na(+)-to-K(+) permeability ratio = 0.007), and were potently inhibited by I(Kr) blockers. Astemizole, terfenadine, cisapride, and MK-499 inhibited cERG and human ERG (hERG) currents with IC(50) values of 1.3, 13, 19, and 15 nM and 1.2, 9, 14, and 21 nM, respectively, and competitively displaced [(35)S]MK-499 binding from cERG and hERG with IC(50) values of 0.4, 12, 35, and 0.6 nM and 0.8, 5, 47, and 0.7 nM, respectively. cERG channels had biophysical properties appropriate for canine action potential repolarization and were pharmacologically sensitive to agents known to prolong QT. A novel MK-499 binding assay provides a new tool to detect agents affecting ERG channels.

Animals↗
PubMed1995

Blockade of K+ channels induced by AMPA/kainate receptor activation in mouse oligodendrocyte precursor cells is mediated by Na+ entry.

AMPA/kainate receptor activation in cultured oligodendrocyte precursor cells from embryonic mouse cortex leads to a blockade of delayed rectifying K+ currents. In the present study, we provide evidence using the patch-clamp technique in the whole-cell configuration that the mechanism linking kainate receptor activation and K+ conductance blockade is due to the receptor-mediated Na+ entry: 1) The blockade was not observed in Na(+)-free bathing solution nor when intracellular [Na+] was elevated by dialzying the cell with a pipette solution containing high [Na+]. 2) Elevation of intracellular [Na+] alone led to a blockade of outward currents in contrast to cells dialyzed by sucrose. High [Li+]i also reduced the outward currents, and in Li(+)-containing bathing solution the kainate-induced blockade of K+ channels was more pronounced. Probably, Li+ accumulates intracellularly after permeation through the receptor pore due to slower extrusion mechanisms. Experiments with GTP gamma S or GDP beta S and pertussis toxin indicated that GTP-binding protein-mediated mechanisms were not of importance for the kainate-induced K+ conductance blockade. Our data suggest that in glial precursor cells AMPA/kainate receptor activation leads to an intracellular [Na+] increase which blocks delayed rectifying K+ channels.

Animals↗