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PubMed1996

Blockade of HERG channels expressed in Xenopus oocytes by the histamine receptor antagonists terfenadine and astemizole.

The widely used histamine receptor antagonists terfenadine and astemizole were shown to prolong the QT interval in electrocardiographic recordings in cases of overdose or inappropriate co-medications, indicating a possible interaction with cardiac K+ channels. Here, terfenadine and astemizole both inhibited the human ether-a-go-go related gene (HERG) encoded channels expressed in Xenopus oocytes at nanomolar concentrations in a use- and voltage-dependent fashion. In contrast, inhibition of other delayed rectifier (Kv1.1 and IsK) or inward rectifier K+ channels (IRK1) was much weaker and occurred only at high micromolar concentrations. These results suggest that blockade of HERG channels by terfenadine and astemizole might contribute to the cardiac side effects of these compounds.

Animals↗
PubMed2002

Ketamine inhibits sodium currents in identified cardiac parasympathetic neurons in nucleus ambiguus.

BACKGROUND: Ketamine increases both blood pressure and heart rate, effects commonly thought of as sympathoexcitatory. The authors investigated the possibility that ketamine increases heart rate by inhibiting the central cardiac parasympathetic mechanisms. METHODS: We used a novel in vitro approach to study the effect of ketamine on the identified cardiac parasympathetic preganglionic neurons in rat brainstem slices. The cardiac parasympathetic neurons in the nucleus ambiguus were retrogradely prelabeled with the fluorescent tracer by placing rhodamine into the pericardial sac. Dye-labeled neurons were visually identified for patch clamp recording, and ketamine effects on isolated potassium (K+) and sodium (Na+) currents were studied. RESULTS: Cardiac nucleus ambiguus neurons (n = 14) were inherently silent, but depolarization evoked sustained action potential trains with little delay or adaptation. Ketamine (10 microm) reduced this response but had no effect on the voltage threshold for action potentials (n = 14; P > 0.05). The current-voltage relations for the transient K+ current and the delayed rectified K+ current (n = 5) were unaltered by ketamine (10 mum-1 mm). Ketamine depressed the total Na+ current dose-dependently (10 microm-1 mm). In addition, ketamine shifted the Na+ current inactivation curves to more negative potentials, thus suggesting the enhancement of the Na+ channel inactivation (P < 0.05; n = 7). In the presence of Cd2+, ketamine (10 mum) continued to inhibit voltage-gated Na+ currents, which recovered completely within 10 min. CONCLUSIONS: Ketamine inhibits Na+ but not K+ channel function in brainstem parasympathetic cardiac neurons, and such actions may mediate the decrease in parasympathetic cardiac activity and increase in heart rate that occurs with ketamine.

Anesthetics, Dissociative↗
PubMed2006

Cardiac glycosides as novel inhibitors of human ether-a-go-go-related gene channel trafficking.

Direct block of the cardiac potassium channel human ether-a-go-go-related gene (hERG) by a large, structurally diverse group of therapeutic compounds causes drug-induced QT prolongation and torsades de pointes arrhythmias. In addition, several therapeutic compounds have been identified more recently that prolong the QT interval by inhibition of hERG trafficking to the cell surface. We used a surface expression assay to identify novel compounds that interfere with hERG trafficking and found that cardiac glycosides are potent inhibitors of hERG expression at the cell surface. Further investigation of digitoxin, ouabain, and digoxin revealed that all three cardiac glycosides reduced expression of the fully glycosylated cell surface form of hERG on Western blots, indicating that channel exit from the endoplasmic reticulum is blocked. Likewise, hERG currents were reduced with nanomolar affinity on long-term exposure. hERG trafficking inhibition was initiated by cardiac glycosides through direct block of Na(+)/K(+) pumps and not via off-target interactions with hERG or another closely associated protein in its processing or export pathway. In isolated guinea pig myocytes, long-term exposure to 30 nM of the clinically used drugs digoxin or digitoxin reduced hERG/rapidly activating delayed rectifier K(+) current (I(Kr)) currents by approximately 50%, whereas three other cardiac membrane currents--inward rectifier current, slowly activating delayed rectifier K(+) current, and calcium current--were not affected. Importantly, 100 nM digitoxin prolonged action potential duration on long-term exposure consistent with a reduction in hERG/I(Kr) channel number. Thus, cardiac glycosides are able to delay cardiac repolarization at nanomolar concentrations via hERG trafficking inhibition, and this may contribute to the complex electrocardiographic changes seen with compounds such as digitoxin.

Action Potentials↗
PubMed1999

Cardiac ultrarapid delayed rectifiers: a novel potassium current family o f functional similarity and molecular diversity.

Classical cardiac delayed rectifier currents activate at least two orders of magnitude slower than delayed rectifier currents in nerve and skeletal muscle tissue. It has recently become evident that many cardiac tissues express delayed rectifier currents with kinetics similar to those of nerve and muscle. These currents have been designated I(Kur) (for 'ultrarapid' delayed rectifier), in contrast to the classical cardiac rapid (I(Kr)) and slow (I(Ks)) delayed rectifier components. Although the kinetics of I(Kur) in different species and tissues are similar, their pharmacological properties vary greatly. It now appears that the differences among various I(Kur)s are due to differences in the molecular basis. A variety of Shaker-related clones (Kv1.2, 1.5, 2.1 and 3.1) that form I(Kur) channels upon heterologous expression have been identified with specific I(Kur)s (e.g. Kv1.2, rat atrium; Kv1.5, mouse ventricle and human atrium; Kv3.1, dog atrium). The present article reviews the distribution, biophysical and pharmacological properties, molecular basis and functional role of I(Kur), as well as the potential value of I(Kur) as a target for new antiarrhythmic drug development.

Animals↗
PubMed1999

Expression of potassium channels during postnatal differentiation of rabbit Müller glial cells.

The postnatal maturation of Müller glial cells from immature radial glial cells is accompanied by specific changes in the activity of distinct types of K+ channels, as shown by whole-cell and cell-attached records on freshly isolated cells from retinae of young (postnatal days 1-30, P1-P30) and adult rabbits. (i) The density of inwardly rectifying currents, providing the main K+ conductance in adult Müller cells, was very low (0.8 pA/pF) from P1 to P6 but increased rapidly thereafter until a relatively stable level of 11.0 pA/pF was established at P17. (ii) Transient (A-type) K+ currents were expressed in all immature cells at a high density (9.6 pA/pF). After P12, both the percentage of cells with A-type currents and the peak amplitudes of the currents (2.8 pA/pF) declined. (iii) Delayed rectifying K+ currents developed slowly until after P30. (iv) The postnatal maturation of radial glial cells was accompanied by a strong decrease in the activity of large-conductance, Ca2+-activated K+ channels, the open probability of which (measured at the resting membrane potential) decreased from 0.69 at P2-4 to 0.06 at P13-14. The developmental decrease of the activity of Ca2+-activated K+ channels is assumed to be mainly caused by alteration of the resting membrane potential which developed from low values (-49 mV) at P1-6 to high adult values (-84 mV) after P13. The activity of each distinct type of K+ channel investigated is differently modulated by developmental regulation. This may reflect different functional requirements of immature and mature Müller cells.

Animals↗
PubMed1995

Effect of captopril on membrane currents of ventricular myocytes.

Using whole-cell patch-clamp technique, the present study examined the effects of captopril on membrane currents of ventricular myocytes. The results were as follow: when the concentration of captopril was 6 x 10(-4)mol, the fast inward sodium current and slow inward calcium current were all decreased significantly (P < 0.05). Besides, when the concentration exceeds 10(-3)mol, the delayed rectifier potassium current was increased (P < 0.05) as well. But if the experimental concentration was under 6 x 10(-4)mol, these three kinds of currents was not affected. These findings suggested that captopril has no direct antiarrhythmic effect at the average therapeutic serum level.

Anti-Arrhythmia Agents↗
PubMed1988

Effects of bupivacaine on membrane currents of guinea-pig ventricular myocytes.

The effects of bupivacaine on the membrane currents of single guinea-pig ventricular myocytes were investigated using the whole-cell patch-clamp technique. Bupivacaine decreased the inward calcium current in a concentration-dependent way at concentrations of 10 microM and higher. Bupivacaine also decreased the delayed outward current without modifying the inward-rectifying potassium current. From these results it can be concluded that bupivacaine, at concentrations lower than 10 microM, does not exert its negative inotropic effect by decreasing the calcium current. This mechanism may play a role at higher concentrations of the drug.

Animals↗
PubMed1996

Oligodendrocyte progenitor cell proliferation and lineage progression are regulated by glutamate receptor-mediated K+ channel block.

We have analyzed the role of glutamate and its receptors (GluRs) in regulating the development of oligodendrocytes. Activation of AMPA-preferring GluRs with selective agonists inhibited proliferation of purified cortical oligodendrocyte progenitor (O-2A) cells cultured with different mitogens, as measured by [3H]thymidine incorporation or bromodeoxyuridine staining. In contrast, activation of GABA or muscarinic receptors did not affect O-2A proliferation. Cell viability and apoptosis assays demonstrated that the inhibition of O-2A proliferation was not attributable to a cytotoxic action of GluR agonists, and was reversible. Activation of GluRs prevented lineage progression from the O-2A (GD3+/nestin+) stage to the prooligodendroblast (O4+) stage, but did not affect O-2A migration. Additional experiments examined the membrane ionic channels mediating these GluR activation effects. We found that proliferating O-2A cells expressed functional delayed rectifier K+ channels, which were absent in pro-oligodendroblasts. GluR agonists and the K+ channel blocker tetraethylammonium (TEA) strongly inhibited delayed rectifier K+ currents in O-2A cells. TEA reproduced the effects of GluR activation on O-2A proliferation and lineage progression in the same concentration range that blocked delayed rectifier K+ currents. These results indicate that glutamate regulates oligodendrogenesis specifically at the O-2A stage by modulating K+ channel activity.

Animals↗
PubMed1996

Outward K+ current in epithelial cells isolated from intermediate portion of endolymphatic sac of guinea pigs.

Ion currents in epithelial cells isolated from the intermediate portion of endolymphatic sac (ES) in guinea pigs were investigated with the use of the whole cell patch-clamp technique. Depolarizing voltage steps from a holding potential of -60 mV induced a time- and voltage-dependent outward current, which is comparable to that of delayed rectifying K+ currents. The average resting membrane potential in the current-clamp mode was -54.8 +/- 11 mV (n = 45), which was similar to the value of zero current potential (-55.6 +/- 0.8 mV, n = 32) obtained from current-voltage (I-V) relationships of outward currents in voltage-clamp mode. The I-V relationship of the tail current exhibited a reversal potential (Erev) of -78.1 +/- 0.9 mV (n = 19) in standard external solution. The Erev of the outward current was linearly related to the logarithm of extracellular K+ concentrations. The slope was 48 mV per 10-fold change in extracellular K+ concentrations. The time constants of K+ current activation, inactivation, and K+ tail current deactivation were voltage dependent. The steady-state activation and inactivation of K+ current exhibited a sigmoidal relationship to voltage. The 50% maximal activation voltage and slope factor were -21 and 11 mV (n = 8), respectively. The 50% maximal inactivation voltage and slope factor were -45 and 13 mV (n = 7), respectively. The K+ current was blocked by externally applied 1 mM 4-aminopyridine (4-AP), 5 mM Ba2+ and 20 mM tetraethylammonium chloride (TEA). The sensitivity of the current to 4-AP and Ba2+ was higher than that to TEA. Elimination of external Ca2+ and increase of internal Ca2+ failed to significantly change the current, suggesting that the K+ current may be Ca2+ independent. The results show that epithelial cells in the intermediate portion of the ES possess a delayed-rectifier K+ current, which may be involved in membrane stability or in the ion balance between the cytosol and the extracellular environment.

Animals↗
PubMed1996

Mechanism of inhibition of delayed rectifier K+ current by 4-aminopyridine in rabbit coronary myocytes.

1. The mechanisms involved in the 4-aminopyridine (4-AP)-induced block of delayed rectifier K+ current (IK(V)) in vascular smooth muscle cells were studied in cells enzymatically isolated from the rabbit coronary artery. 2. 4-AP inhibited slowly inactivating IK(V) in a dose-dependent manner (concentration producing half-maximal inhibition, K1/2, = 1.37 mM), and shifted the steady-state activation and inactivation curves of IK(V) by +9 and +16 mV, respectively. 3. The time constant of activation was significantly increased by 4-AP at +20 mV; deactivation kinetics were unaffected upon repolarization to -40 mV. The fast (tau f approximately 1 s) and slow (tau s approximately 5 s) time constants of inactivation (0 and +20 mV), and the recovery kinetics (tau r approximately 6 s) at -60 mV were not significantly affected by 0.5 mM 4-AP. However, tau f disappeared in the presence of 2 mM 4-AP while tau s remained unaffected. 4. Use-dependent unblock of IK(V) was revealed at potentials > or = -10 mV from analyses of the voltage dependence of 4-AP-sensitive currents and the frequency-dependent changes ('reverse use dependence') of IK(V) during the application of repetitive steps (-60 to +20 mV for 250 ms at a rate of 0.25 Hz) in control conditions, in the presence of 0.5 mM 4-AP, and after washout of the drug. These results suggested that 4-AP preferentially binds to the channel in the closed state, and unbinding is promoted by transitions to the open state. 5. The channel was modelled as a simple three-state mathematical loop model incorporating single closed, open and inactivated states. The block by 4-AP was modelled as a state-dependent interaction with 4-AP primarily binding to the closed state. Computer simulations support the hypothesis that 4-AP-induced block of the delayed rectifier K+ (KV) channel in the closed state is relieved during membrane depolarization. 6. Closed state binding of 4-AP to the KV channel depolarizes vascular smooth muscle cells by shifting the activation curve of these channels to more positive potentials.

4-Aminopyridine↗
PubMed2006

Donepezil is a strong antagonist of voltage-gated calcium and potassium channels in molluscan neurons.

Donepezil is an acetylcholinesterase inhibitor used in Alzheimer's disease therapy. The neuroprotective effect of donepezil has been demonstrated in a number of different models of neurodegeneration including beta-amyloid toxicity. Since the mechanisms of neurodegeneration involve the activation of both Ca(2+)- and K(+)-channels, the study of donepezil action on voltage-gated ionic currents looked advisable. In the present study, the action of donepezil on voltage-gated Ca(2+)- and K(+)-channels was investigated on isolated neurons of the edible snail (Helix pomatia) using the two-microelectrodes voltage-clamp technique. Donepezil rapidly and reversibly inhibited voltage activated Ca(2+)-current (I(Ca)) (IC(50)=7.9 microM) and three types of high threshold K(+)-current: Ca(2+)-dependent K(+)-current (I(C)) (IC(50)=6.4 microM), delayed rectifier K(+)-current (I(DR)) (IC(50)=8.0 microM) and fast transient K(+)-current (I(Adepol)) (IC(50)=9.1 microM). The drug caused a dual effect on low-threshold fast transient K(+)-current (I(A)), potentiating it at low (5 microM) concentration, but inhibiting at higher (7 microM and above) concentration. Donepezil also caused a significant hyperpolarizing shift of the voltage-current relationship of I(Ca) (but not of any type of K(+)-current). Results suggest the possible contribution of the blocking effect of donepezil on the voltage-gated Ca(2+)- and K(+)-channels to the neuroprotective effect of the drug.

Animals↗
PubMed1991

A fast, transient K+ current in neurohypophysial nerve terminals of the rat.

1. Nerve terminals of the rat posterior pituitary were acutely dissociated and identified using a combination of morphological and immunohistochemical techniques. Macroscopic terminal membrane currents and voltages were studied using the whole-cell patch clamp technique. 2. In physiological solutions, depolarizing voltage clamp steps, from a holding potential (-80 mV) similar to the normal terminal resting potential, elicited a fast, inward followed by a fast, transient, outward current. 3. The threshold of activation for the outward current was -60 mV. The outward current quickly reached a peak and then decayed more slowly. The decay was fitted by two exponentials with time constants of 21 +/- 2.9 and 143 +/- 36 ms. These decay constants did not show a dependence on voltage. The time to peak of the outward current decreased and the amplitude increased with increasingly depolarized potential steps. 4. The outward current was blocked by the substitution of K+ with Cs+ and its reversal potential was consistent with a potassium current. 5. The transient outward current showed steady-state inactivation at more depolarized (than -80 mV) holding potentials with 50% inactivation occurring at -47.9 mV. The time course of recovery from inactivation was complex with full recovery taking greater than 16 s. 6. 4-Aminopyridine (4-AP) blocked the transient outward current in a dose-dependent manner (approximately IC50 = 3 mM), while charybdotoxin (4 micrograms/ml) and tetraethylammonium (100 mM) had no effect on the current amplitude. 7. Lowering external [Ca2+] had no effect on the fast, transient outward current nor did the calcium channel blocker Cd2+ (2 mM). 8. The neurohypophysial outward current reported here corresponds most closely to IA, and not to the delayed rectifier or Ca2(+)-activated K+ currents. Neurohypophysial IA, however, appears to be different from the outward currents found in the cell bodies in the hypothalamus which project their axons to the posterior pituitary. 9. Under current clamp, evoked action potential duration increased (122%) upon application of 5 mM-4-AP, indicating that IA is involved in neurohypophysial spike repolarization. 10. The existence of this current could help explain why maximal peptide release only occurs in response to bursts of electrical activity invading the nerve terminals.

4-Aminopyridine↗
PubMed1994

Presynaptic modulation by eicosanoids in cortical synaptosomes.

In continuing experiments to determine the ionic basis of inhibitory presynaptic modulation, rat cortical synaptosomes were employed and receptor-activated K+ efflux was determined with a K+ sensitive electrode. When synaptosomes were sub-optimally depolarized by veratridine, the addition of agents that activated purinergic, alpha 2-adrenergic, muscarinic and opioid receptors all promoted K+ efflux. With 2-chloroadenosine as a model inhibitory presynaptic modulator, the increased K+ efflux evoked by this agent was blocked by the cyclooxygenase inhibitor indomethacin suggesting that arachidonic acid or its metabolites was an intermediary in opening the channel. When arachidonic acid and PGE2 were tested, both promoted K+ efflux that was inhibited by dendrotoxin and mast cell degranulating peptide, two agents that are known to inhibit a delayed rectifier K+ current. Our results suggest that via eicosanoid second messengers, inhibitory presynaptic modulators open a sub-class of K channels that hyperpolarize nerve terminals, therefore less Ca2+ would enter per nerve impulse and thus the evoked release of neurotransmitters would be decreased.

Animals↗
PubMed1999

Odorant suppression of delayed rectifier potassium current in newt olfactory receptor cells.

Effects of odorants on a delayed rectifier potassium current (IK) in newt olfactory receptor cells (ORCs) were investigated using the whole-cell version of the patch-clamp technique. Under voltage clamp, odorants (amyl acetate, limonene and acetophenone) reversibly suppressed I(K) without shifting its I-V curve. An amyl acetate puff completely suppressed I(K) induced by the first step pulse of repetitive depolarizations, suggesting that binding of an odorant molecule to the open channel is not required to block the channel. Although it is known that odorants suppress Na+ and Ca2+ currents (I(Na), I(Ca)) by shifting their inactivation curves to a negative voltage, odorants did not shift the inactivation curve of I(K) significantly. This suggests that odorants suppress I(K) without changing its voltage dependence. Therefore, the blocking mechanisms by odorants of I(K) in ORCs are different from those of I(Na) and I(Ca).

Acetophenones↗
PubMed1995

KCa channel antagonists reduce NO donor-mediated relaxation of vascular and tracheal smooth muscle.

Electrophysiological studies suggest that activation of large-conductance Ca-activated K channels (KCa) with nitric oxide (NO) causes hyperpolarization and relaxation of smooth muscle. We determined whether KCa blockers decreased relaxation to the NO donors S-nitroso-N-acetylpenicillamine (SNAP) and 3-morpholinosydonimine-hydrochloride (SIN-1) in isolated segments from main pulmonary artery (MPA), its left branch (LPA), aorta (Ao), carotid artery (CA), and trachea (Tr). NO donors caused concentration-dependent relaxation of tissues precontracted with histamine whereas the inactive carrier molecule C88-3934 was without effect. The rank order profiles of SNAP and SIN-1 sensitivity were CA = Ao = MPA > LPA = Tr. Compared with histamine, 80 mM KCl precontraction caused variable reductions in tissue sensitivity and maximum relaxation to SNAP. The KCa antagonists charybdotoxin, iberiotoxin, and tetraethylammonium decreased sensitivity to SNAP and SIN-1 2- to 11-fold in MPA, LPA, and Tr, with variable shifts in Ao and CA. The effect of iberiotoxin was not altered by removing the endothelium or epithelium. Furthermore, charybdotoxin or iberiotoxin did not alter basal or SNAP-stimulated guanosine 3',5'-cyclic monophosphate content. Glibenclamide, noxiustoxin, and leiurotoxin I, antagonists of ATP-dependent, delayed rectifier, and small-conductance KCa channels, respectively, had no effect. In conclusion, antagonists of KCa decrease NO donor-mediated relaxation of pulmonary arterial and tracheal smooth muscle.

Animals↗
PubMedDate not supplied

Voltage-clamp analysis and computational model of dopaminergic neurons from mouse retina.

Isolated dopaminergic amacrine (DA) cells in mouse retina fire rhythmic, spontaneous action potentials and respond to depolarizing current with trains of low-frequency action potentials. To investigate the roles of voltage-gated ion channels in these processes, the transient A-type K+ current (I(K,A)) and Ca2+ current (I(Ca)) in isolated mouse DA cells were analyzed by voltage clamp. The I(K,A) activated at -60 mV and inactivated rapidly. I(Ca) activated at around -30 mV and reached a peak at 10 mV without apparent inactivation. We also extended our previous computational model of the mouse DA cell to include the new electrophysiological data. The model consisted of a membrane capacitance in parallel with eight currents: Na+ transient (I(Na,T)), Na+ persistent (I(Na,P)), delayed rectifier potassium (I(Kdr)), I(K,A), calcium-dependent potassium (I(K,Ca)), L-type Ca2+ I(Ca), hyperpolarization-activated cation current (I(h)), and a leak current (I(L)). Hodgkin-Huxley type equations were used to define the voltage- and time-dependent activation and inactivation. The simulations were implemented using the neurosimulator SNNAP. The model DA cell was spontaneously active from a wide range of initial membrane potentials. The spontaneous action potentials reached 35 mV at the peak and hyperpolarized to -76 mV between spikes. The spontaneous firing frequency in the model was 6 Hz. The model DA cell responded to prolonged depolarizing current injection by increasing its spiking frequency and eventually reaching a depolarization block at membrane potentials greater than -10 mV. The most important current for determining the firing rate was I(K,A). When the amplitude of I(K,A) was decreased, the firing rate increased. I(Ca) and I(K,Ca) also affected the width of action potentials but had only minor effects on the firing rate. Ih affected the firing rate slightly but did not change the waveform of the action potentials.

Action Potentials↗
PubMed1987

Effect of channel blockers on potassium efflux from metabolically exhausted frog skeletal muscle.

1. 86Rb and 42K have been used to assess potassium exchange in frog skeletal muscle which had been metabolically exhausted by electrical stimulation (1 Hz) after treatment with 2 mM-cyanide and 1 mM-iodoacetate. These conditions led to the development of rigor. 2. Poisoning by itself induced a small but variable increase in tracer efflux. Complete mechanical exhaustion subsequent to electrical stimulation was, however, accompanied by a 5-6 fold increase in the rate coefficient for both 86Rb and 42K efflux. In the case of rubidium this was maintained for at least 20 min and often for up to 1 h. 3. The increase in tracer efflux induced by metabolic exhaustion was inhibited by barium (0.03-5 mM) in a reversible and concentration-dependent manner. Inhibition was also observed with glibenclamide (3-100 microM), tolbutamide (0.3-2 mM), TEA (5-100 mM) and the local anaesthetics lignocaine (1-3 mM) and tetracaine (1 mM). Quinine produced a dual response consisting of an inhibitory component which was most clearly seen at low concentrations (0.3 mM) and an enhancement of tracer efflux that became increasingly dominant at higher concentrations (1-10 mM). 4. Both apamin (30 and 100 nM) and Israeli scorpion (Leiurus quinquestriatus) venom (16 micrograms ml-1) produced little or no block of the tracer efflux activated by metabolic exhaustion. Similarly 4-aminopyridine (3 mM) and decamethonium (0.3 mM) were without obvious effect. 5. It is concluded that metabolic exhaustion of frog skeletal muscle leads to an increased permeability to both 42K and 86Rb. Our results with channel blockers suggest that this K+ permeability can be attributed neither to the delayed rectifier nor to an apamin- or charybdotoxin-sensitive calcium-activated K+ permeability (PK(Ca) but may be predominantly due to activation of ATP-sensitive channels similar to those found in the beta-cells of pancreatic islets.

4-Aminopyridine↗
PubMed2004

Molecular cloning, genomic organization and functional characterization of a new short-chain potassium channel toxin-like peptide BmTxKS4 from Buthus martensii Karsch(BmK).

Scorpion venom contains many small polypeptide toxins, which can modulate Na(+), K(+), Cl(-), and Ca(2+) ion-channel conductance in the cell membrane. A full-length cDNA sequence encoding a novel type of K(+)-channel toxin (named BmTxKS4) was first isolated and identified from a venom gland cDNA library of Buthus martensii Karsch (BmK). The encoded precursor contains 78 amino acid residues including a putative signal peptide of 21 residues, propeptide of 11 residues, and a mature peptide of 43 residues with three disulfide bridges. BmTxKS4 shares the identical organization of disulfide bridges with all the other short-chain K(+)-channel scorpion toxins. By PCR amplification of the genomic region encoding BmTxKS4, it was shown that BmTxKS4 composed of two exons is disrupted by an intron of 87 bp inserted between the first and the second codes of Phe (F) in the encoding signal peptide region, which is completely identical with that of the characterized scorpion K(+)-channel ligands in the size, position, consensus junctions, putative branch point, and A+T content. The GST-BmTxKS4 fusion protein was successfully expressed in BL21 (DE3) and purified with affinity chromatography. About 2.5 mg purified recombinant BmTxKS4 (rBmTxKS4) protein was obtained by treating GST-BmTxKS4 with enterokinase and sephadex chromatography from 1 L bacterial culture. The electrophysiological activity of 1.0 microM rBmTxKS4 was measured and compared by whole cell patch-clamp technique. The results indicated that rBmTxKS4 reversibly inhibited the transient outward K(+) current (I(to)), delayed inward rectifier K(+) current (I(k1)), and prolonged the action potential duration of ventricular myocyte, but it has no effect on the action potential amplitude. Taken together, BmTxKS4 is a novel subfamily member of short-strain K(+)-channel scorpion toxin.

Amino Acid Sequence↗