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Query: UNIPROT:P06889 (Mol)
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The binding of labeled batrachotoxinin-A benzoate (BTX-B) to voltage-sensitive sodium channels in broken membrane preparations of mouse cerebral cortex has been measured as a function of the pH. Specific binding is negligible at pH less than 6.0, maximum at pH 8.5, and decreases again at pH 9.0. A major component of nonspecific binding, however, increases linearly in the pH range 7.0-9.0. The pKa of batrachotoxinin-A, an analogue of BTX-B, was found by titrimetric methods to be greater than or equal to 8.2. Analysis of the data shows that at least part of the pH dependence of BTX-B binding is due to the titration of a sodium channel residue(s) associated in some way with the BTX-B recognition site. The possible involvement of a histidine residue is suggested.
Cell Mol Neurobiol 1981 Dec
PMID:Interaction of batrachotoxinin-A benzoate with voltage-sensitive sodium channels: the effects of pH. 610 Oct 82

Various histrionicotoxins tested on frog nerve-muscle preparations showed a qualitative family resemblance to one another. They blocked the nerve-evoked muscle twitch and depressed both the peak amplitudes and the decay time constants of end-plate currents. During repetitive stimulation they progressively decreased the rate of rise and prolonged the falling phase of muscle action potentials, the latter resulting, at least in part, from blockade of voltage-sensitive potassium channels. These results indicated that the histrionicotoxins act at three membrane channels: the channel associated with the acetylcholine receptor, the sodium channel, and the potassium channel. Closer study of perhydrohistrionicotoxin suggested either two topographically distinct sites of action at the acetylcholine receptor-ion channel complex, or one site and two ion channel complex conformations. One site or conformation only alters the kinetics of channel closure. As these sites become saturated, the end-plate current decay time constant asymptotically approaches a limiting value. The other site or conformation prevents the channel from opening altogether. Further analysis indicated that the binding site for perhydrohistrionicotoxin that alters the kinetics of channel closure has an affinity constant of 0.1 microM-1 at -90 mV and that this affinity may be sensitive to the membrane potential. The lipid protein interface is a suggested site of histrionicotoxin action, common to the three channels studied here as well as to other intrinsic membrane proteins affected by histrionicotoxins.
Mol Pharmacol 1982 Mar
PMID:Actions of the histrionicotoxins at the ion channel of the nicotinic acetylcholine receptor and at the voltage-sensitive ion channels of muscle membranes. 628 71

Variant neuroblastoma cell clones were selected for resistance to the cytotoxic effects of neurotoxins that cause persistent activation of sodium channels. Three classes of variant clones were obtained: sodium channel-deficient clones, which have markedly reduced numbers of functional sodium channels; scorpion toxin-resistant clones, which have sodium channels with an altered interaction with scorpion toxin; and parental-type clones, which have functional sodium channels similar to the ones from N18 cells but have other heritable alterations that confer toxin resistance. The frequency of conversion to all three variant phenotypes was enhanced by treatment with the missense mutagen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), suggesting that all three variant phenotypes are the result of mutational events. Incorporation of [35S]methionine into the alpha-subunit of the sodium channel (Mr = 270,000; pI = 5.8 +/- 0.2) was studied in normal and variant clones by affinity chromatography on wheat germ agglutinin/Sepharose followed by analysis of labeled polypeptides by 1- and 2-dimensional gel electrophoresis. Sodium channel-deficient clones do not synthesize the alpha-subunit of the sodium channel, suggesting that mutations in these clones block expression of the gene for this protein subunit. The scorpion toxin-resistant clone LV10 synthesizes an alpha-subunit which has a molecular weight and pI similar to those of the parental clones within the resolution of the methods used.
Mol Pharmacol 1982 Jul
PMID:Characterization of variant neuroblastoma clones with missing or altered sodium channels. 628 70

The temperature-sensitive paralytic mutant of Drosophila, napts, has been shown to have defects in axonal physiology which suggest that it codes for a component of the voltage-sensitive sodium channel. Ligand binding studies using tritiated tetrodotoxin, a sodium channel antagonist, show a decrease in the apparent number of sodium channels in napts, providing additional support for this hypothesis.
Mol Gen Genet 1982
PMID:Reduced [3H]-tetrodotoxin binding in the napts paralytic mutant of Drosophila. 629 70

The sodium channel-specific agent batrachotoxin (BTX) has been shown to induce a time- and concentration-dependent depolarization of a vesicular preparation from guinea pig cerebral cortex. The K0.5 for depolarization by BTX was 0.011 microM at 30 min. Membrane potential was determined by the equilibrium distribution of [3H]triphenylmethylphosphonium ion. A series of seven local anesthetics was shown to inhibit BTX-induced depolarization competitively with Ki values ranging from 0.9 microM for dibucaine to 780 microM for lidocaine ethiodide. The specific binding of labeled batrachotoxinin-A 20 alpha-benzoate ([3H]BTX-B) to voltage-sensitive channels in vesicular preparations from mouse cerebral cortex in the presence of scorpion venom was measured and found to yield a range of Kd values from 25 to 30 nM and Bmax values of 0.5 and 1.0 pmole/mg of protein; the same preparation from guinea pig cerebral cortex was found to yield Kd values from 13 to 56 nM and Bmax values of 0.8-2.2 pmoles/mg of protein. A series of 14 local anesthetics was shown to inhibit the specific binding of [3H]BTX-B with Ki values ranging from 0.6 microM for dibucaine to 400 microM for benzocaine. The rank order of potency of the local anesthetics as antagonists of [3H]BTX-B binding was as follows: dibucaine greater than tetracaine greater than bupivacaine greater than diphenhydramine greater than piperocaine greater than cocaine greater than procaine greater than lidocaine greater than benzocaine. The quaternary local anesthetic dimethyl-di(phenylcarbamoylmethyl)ammonium chloride was comparable in potency to tetracaine. The rank order and relative potency of the local anesthetics tested in both paradigms were similar with the exception of lidocaine ethiodide, which was 18 times more potent as an inhibitor of binding of [3H]BTX-B than it was as an inhibitor of BTX-elicited depolarization.
Mol Pharmacol 1983 Mar
PMID:Batrachotoxin-induced depolarization and [3H]batrachotoxinin-a 20 alpha-benzoate binding in a vesicular preparation from guinea pig cerebral cortex. 630 Jun 44

Several different toxins having specific effects on the kinetics of sodium channels have been isolated from the venoms of two scorpions. A combination of two steps of ion-exchange chromatography has been used to purify these toxins, whose sizes and purities have been assayed by gel filtration, urea/sodium dodecyl sulfate/polyacrylamide gel electrophoresis, and isoelectric focusing. The actions of the toxins and their relative potencies have been determined by studying the modifications they produce in action potential shape, using the sucrose-gap method, and in ionic current kinetics, measured under voltage-clamp, both assays performed on myelinated axons of frogs and toads. The venom of Leiurus quinquestriatus scorpions yielded two active neurotoxins; the major neurotoxin has a mass of approximately 7000 daltons. This major toxin affected the sodium channel inactivation process exclusively, slowing the rates of inactivation as well as preventing complete inactivation from occurring in some of the channels. Such slowed and incomplete sodium inactivation resulted in action potentials that were prolonged, from their usual duration of 5-8 msec to hundreds of milliseconds or even seconds. Five toxins were isolated from the venom of Centruroides sculpturatus Ewing scorpions, all of which also had masses of approximately 7000-7500 daltons. Four of these toxins acted primarily on the activation process of sodium channels, producing a novel increase in sodium permeability upon repolarization of the nerve membrane following a depolarizing pulse, as previously described for the crude venom [Cahalan, M. D. J. Physiol. (Lond.) 244:511-534 (1975)]. These toxins also caused repetitive firing of action potentials in single axons in response to one stimulating pulse, as well as spontaneous impulse firing. A fifth neurotoxin from C. sculpturatus venom had effects similar to those of the L. quinquestriatus toxins, slowing and preventing complete sodium inactivation. The effect of this toxin was slowly removed during external perfusion by Ringer's solution.
Mol Pharmacol 1983 Mar
PMID:Purification and physiological characterization of neurotoxins from venoms of the scorpions centruroides sculpturatus and leiurus quinquestriatus. 630 Jun 54

The effects of several local anesthetics on the binding of ligands to receptors associated with voltage-sensitive sodium channels in rat brain synaptosomes have been examined. In the presence of 0.3 microM scorpion toxin, the 13 local anesthetics tested inhibited the specific binding of [3H]batrachotoxinin A 20 alpha-benzoate [( 3H]BTX-B), a ligand which binds to a receptor site responsible for the activation of sodium channel ion flux, in a dose-dependent fashion, with KD values ranging from 1.2 microM for tetracaine to 1.58 mM for benzocaine. A plot of log KD from these binding experiments against log K0.5 for inhibition of sodium currents by local anesthetics from electrophysiological experiments yielded a regression line with a slope of 0.84 and a correlation coefficient, r, of 0.86, demonstrating that the inhibition of [3H]BTX-B binding by local anesthetics occurs within a concentration range of physiological relevance. Tetracaine had little effect on basal 125I-labeled scorpion toxin binding to synaptosomes in the absence of batrachotoxin. However, in the presence of batrachotoxin, tetracaine inhibited the batrachotoxin-dependent increase in scorpion toxin binding (KD = 2.0 microM) in a dose-dependent manner, suggesting that inhibition of [3H]BTX-B binding by local anesthetics does not occur through binding at the scorpion toxin binding site. The inhibition of [3H]BTX-B binding by lidocaine was reversible within 30 min when samples were diluted from 10(-3)M to 10(-4) M lidocaine. Scatchard analysis of [3H]BTX-B binding to synaptosomes showed that bupivacaine and tetracaine reduced receptor affinity without decreasing maximal binding capacity. This reduction in receptor affinity in the presence of local anesthetics appears to be due, at least in part, to an increased rate of ligand dissociation from the receptor-ligand complex, suggesting an indirect allosteric mechanism for the inhibition of [3H]BTX-B binding by local anesthetics. Analysis of the effects of local anesthetics in terms of an allosteric model of drug action showed that they bind to inactive states of sodium channels with at least a 10-fold higher affinity than active states. A 7-fold difference in KD for inhibition of [3H]BTX-B binding between the local anesthetic stereoisomers RAC 109 I and RAC 109 II was observed. Similarly, the dissociation rate constant for the [3H]BTX-B/receptor complex was increased 9.3-fold in the presence of RAC 109 II and 4.3-fold in the presence of a comparable concentration of RAC 109 I.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Pharmacol 1984 Mar
PMID:Inhibition of binding of [3H]batrachotoxinin A 20-alpha-benzoate to sodium channels by local anesthetics. 632 44

The inhibitory action of a number of clinically effective anticonvulsants on neurotoxin-activated sodium channels in cultured neuroblastoma cells and rat brain synaptosomes has been examined. Diphenylhydantoin (KI = 35 microM) and carbamazepine (KI = 41 microM) inhibited batrachotoxin-activated 22Na+ influx in N18 cells. Similarly, batrachotoxin-activated 22Na+ influx in rat brain synaptosomes was also inhibited by diphenylhydantoin (KI = 38 microM) and carbamazepine (KI = 22 microM). Comparison of KI values with mean brain levels of these drugs achieved during prevention of electroshock seizures indicates that diphenylhydantoin and carbamazepine occupy 35% and 50%, respectively, of their receptor sites associated with sodium channels at mean therapeutic concentrations. Diazepam (KI = 51 to 63 microM) and phenobarbital (KI = 1.2 to 1.3 mM) inhibited batrachotoxin-activated 22Na+ flux in N18 cells and synaptosomes at concentrations in excess of mean therapeutic central nervous system levels. Carbamazepine, like diphenylhydantoin, acts as a competitive inhibitor of sodium channel activation by the full agonist batrachotoxin, but produces mixed inhibition of veratridine-activated channels. This finding is consistent with the conclusion that both carbamazepine and diphenylhydantoin act as allosteric inhibitors of neurotoxin-activated sodium channels. The dose-response relationships for carbamazepine and diphenylhydantoin inhibition of 22Na+ flux in N18 cells are shifted 1.5-fold to higher concentrations when 22Na+ flux measurements are made in the presence of physiological concentrations of sodium and calcium ions. These results suggest that anticonvulsant inhibition of neurotoxin-activated 22Na+ flux in our standard ion flux media, containing low concentrations of Na+ and no Ca2+, is likely to reflect an effect of these agents expected in vivo. The results of this study provide further evidence to support the hypothesis that diphenylhydantoin and carbamazepine, both of which possess similar therapeutic profiles in the treatment of grand mal and partial seizures, may exert their pharmacological effects by occupancy of receptor sites associated with the activation of voltage-sensitive sodium channels in the central nervous system.
Mol Pharmacol 1984 Mar
PMID:Inhibition of voltage-sensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine. 632 45

Effects of mexiletine on the rapid inward sodium current (INa) were studied in freshly isolated single cells of the ventricular myocardium of adult rats and in single cultured ventricular muscle cells of newborn rats. The current was measured in internally perfused, voltage-clamped cells by a single suction pipette technique. Mexiletine was applied extracellularly. INa was reduced by the drug in both preparations when the membrane was depolarized to -20 mV by short (8 ms) pulses delivered at a frequency of 0.1 Hz from a holding potential of -100 mV. Mexiletine in a concentration of 50 microM diminished the INa under this condition by 70 +/- 8% (mean +/- S.D.) in the adult myocardial cells. A nearly equal reduction of the current (65 +/- 10%) was caused in the neonatal myocardial cells by 15 microM mexiletine. A use-dependent block of INa was produced in the presence of 10 and of 20 to 30 microM mexiletine, respectively, in the neonatal and the adult myocardial cells by repetitive depolarizing test pulses applied at frequencies between 1 and 7 Hz. Prolongation of the pulse duration from 10 to 100 ms enhanced the use-dependent block of INa in both preparations. The frequency-dependent action of mexiletine could be modulated by 100-ms hyperpolarizing prepulses from -80 to -140 mV. The time course of the use-dependent block (prepulse off) and unblock (prepulse on) was monitored. The slope of the inactivation curve of INa in the neonatal heart cells was reduced in the presence of mexiletine and the midpoint of the curve was shifted in the hyperpolarizing direction. These findings are interpreted as suggesting that binding of mexiletine to the sodium channel of the rat myocardial cells studied is enhanced when the cell membrane becomes depolarized.
J Mol Cell Cardiol 1983 Jul
PMID:Sodium current in freshly isolated and in cultured single rat myocardial cells: frequency and voltage-dependent block by mexiletine. 662 Mar 95

The phenomenon of knockdown resistance (kdr) was first noted in the housefly (Musca domestica), and has subsequently be found (i.e. kdr-type resistance) in several other insect pests including the German cockroach (Blattella germanica). This type of resistance causes insensitivity of the nervous system to pyrethroids, DDT and a limited number of sodium channel neurotoxins. In the German cockroach, kdr-type resistance is incompletely recessive, monogenic and not sex linked or due to cytoplasmic factors. Additionally, kdr-type resistance is not associated with a change in sodium channel density. kdr or kdr-type loci are tightly linked or identical to the para-homologous sodium channel locus in German cockroach, housefly and tobacco budworm (Heliothis virescens), suggesting that kdr and kdr-type resistance are due to mutations in the para-homologous sodium channel gene. kdr-Type resistance in the German cockroach appears similar, although not necessarily identical, to kdr in houseflies.
Comp Biochem Physiol B Biochem Mol Biol
PMID:kdr-Type resistance in insects with special reference to the German cockroach, Blattella germanica. 755 40


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