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PubMed1984

Effect of various cations and anions on the action of tetrodotoxin and saxitoxin on frog myelinated nerve fibers.

The influence of Mg2+, La3+, NO-3, and SCN- on the equilibrium effect of tetrodotoxin (TTX) and saxitoxin (STX) on single myelinated nerve fibres of the frog Rana esculenta was studied under voltage clamp conditions. Mg2+ and La3+ reduce the sodium permeability, shift the voltage dependence of the Na permeability PNa towards more positive potentials and reduce the effectiveness of TTX and STX. NO-3 and SCN- reduce the sodium permeability too, but shift the voltage dependence of PNa towards more negative potentials and increase the action of TTX and STX. In all experiments the change in effectiveness is larger for the divalent STX than for the monovalent TTX. It is concluded that changes of the monovalent TTX. It is concluded that changes of the external surface potential induced by Mg2+, La3+, NO-3 and SCN- affect the TTX and STX binding to toxin receptors. The apparent potential change at the toxin receptor is only a fraction of the change "seen' by the Na channel gates.

Animals↗
PubMed1976

Saxitoxin and procaine act independently on separate sites of the sodium channel.

1. Voltage clamp experiments were done on single myelinated nerve fibres of the frog, Rana esculenta. 2. The time course of procaine action (1.0 mM at pH 7.2) was obtained from changes in INa on changing solutions during repetitive (1 HZ) depolarizing pulses of constant amplitude following hyperpolarizing prepulses. The mean half times of onset and offset of procaine block were 3.7 and 28 s, respectively. In the presence of 1.4 nM saxitoxin (STX) the corresponding times were virtually the same, 3.1 and 27 s. 3. Similarly, the time course of partial relief from procaine block that is obtained by increasing the frequency of the prepulse-test pulse pairs from 1-10 HZ was unaffected in the presence of STX. 4. Comparison of the equilibrium effects of procaine concentrations ranging from 0.03-1.0 mM suggest a one-to-one drug-receptor reaction. The fraction of Na channels blocked at equilibrium with 1.0 mM procaine, 1.4 nM STX, and 1.0 mM procaine + 1.4 nM STX was 0.81, 0.49, and 0.90, respectively. This result and the kinetic behaviour fully agree with the idea of two separate and independent receptors for procaine and STX.

Animals↗
PubMed1991

Use-dependent block with tetrodotoxin and saxitoxin at frog Ranvier nodes. I. Intrinsic channel and toxin parameters.

The use-dependent phasic blockage of sodium channels by tetrodotoxin (TTX) and saxitoxin (STX) was examined in frog nodes of Ranvier using trains of depolarizing pulses. The decline of the peak Na+ current from its initial value (I0) before the train to a stationary value (I infinity) after the train was more pronounced at more negative holding potentials. The relationship between I infinity/I0 and holding potential was fitted by a sigmoid function which yielded values for the steepness of the voltage dependencies of around -15 mV for TTX and -8 mV for STX. Similar values were obtained at toxin concentrations of 4 and 8 nM. The higher voltage sensitivity of STX versus TTX is interpreted in terms of the higher charge and the faster binding kinetics of STX. These differences also explain the frequency dependence of the decline of Na+ currents with STX (between 0.5 and 2 Hz) and the frequency independence with TTX. Variation of the pulse amplitude in a train of conditioning pulses revealed that the magnitude of the use-dependent actions of STX parallels the steady-state Na+ inactivation curve h infinity. Inhibition of inactivation, by pre-treatment with chloramine-T, did not, however, abolish the use dependence. Instead, it introduced a change in the time constants of the decline of the Na+ currents and the magnitude became independent of the holding potential.

Animals↗
PubMed1991

Use-dependent block with tetrodotoxin and saxitoxin at frog Ranvier nodes. II. Extrinsic influence of cations.

Use-dependent declines of Na+ currents in myelinated frog nerve fibres were measured during a train of depolarizing pulses in solutions containing tetrodotoxin (TTX) or saxitoxin (STX). The following effects of external monovalent (Na+), divalent (Ca2+, Mg2+) and trivalent (La3+) cations on use dependence were found: Increasing the Ca2+ concentration from 2 to 8 mM shifts its voltage dependence by 20 mV whereas no significant use-dependent decline occurred at 0.2 mM Ca2+. Doubling the external Na+ concentration in 0.2 mM Ca2+ solutions did not initiate phasic block. External Mg2+ ions induced a smaller, and La3+ ions a larger, use dependence. The time constants of the current decline were 4-fold greater in 1.08 mM La3+. The static block of Na+ currents by La3+ could be directly demonstrated by the relief of block during a train of pulses. The results are qualitatively explained by a toxin binding site at the Na+ channel whose affinity for TTX or STX depends on 1) the gating conformation of the channel, probably the inactivation and ii) the occupancy of a blocking site by di- or trivalent external cations.

Animals↗
PubMed1991

Lack of specific saxitoxin binding to rat mast cells.

We studied whether or not mast cells are endowed with specific sodium channels, by using tritiated saxitoxin which binds to site 1 of sodium channels on excitable tissues. Our results suggest that rat pleural and peritoneal mast cells lack specific sodium channels.

Animals↗
PubMed1989

Use-dependent block of sodium channels in frog myelinated nerve by tetrodotoxin and saxitoxin at negative holding potentials.

Na+ currents were measured in myelinated frog nerve fibres in the presence of nanomolar concentrations of tetrodotoxin (TTX) or saxitoxin (STX) in the extracellular solution. The Na+ currents declined during a train of depolarizing pulses if the fibre was held at hyperpolarizing potentials between the pulses. At a pulse frequency of 0.8 Hz, the peak Na+ currents were reduced to 70 or 60% of the initial value in 9.3 nM TTX and 3.5 nM STX solutions, respectively. A decline of Na+ currents was also observed in two-pulse experiments. The peak Na+ current during a second test pulse did not depend on the duration (0.2 to 12 ms) of the first pulse. It decreased with increasing interval between the pulses, reached a minimum and increased again. The results are interpreted with a use-dependent blockage of Na+ channels by TTX or STX at negative holding potentials. The effects were described quantitatively, assuming a fast affinity increase of toxin receptors at Na+ channels triggered by Na+ activation followed by slow toxin binding to channels and relaxation of the receptor affinity.

Animals↗
PubMed1989

Binding of tetrodotoxin and saxitoxin to Na+ channels at different holding potentials: fluctuation measurements in frog myelinated nerve.

The number of available Na+ channels in nodes of frog nerve fibres was determined from nonstationary Na+ current fluctuations recorded during a train of depolarizing test pulses. Mean numbers in Ringers's solution were 90,000 at a hyperpolarizing holding potential VH = -40 mV, 50,000 at the resting potential (VH = 0 mV) and 30,000 at a depolarizing holding potential VH = 30 mV. Addition of the cationic channel blockers tetrodotoxin (TTX) or saxitoxin (STX) to Ringer reduced the channel number by a factor which was independent of the holding potential. The reduction factor was 4 for 9.3 nM TTX and 3 for 3.5 nM STX. Thus, in the state of repetitive stimulation, TTX or STX blockage of Na+ channels is hardly affected by the membrane potential. Taking into account use-dependent TTX and STX effects [1], it is concluded that binding of both toxins exhibits a weak voltage dependence with toxin affinities decreasing at more negative holding potentials. The results suggest that binding of TTX and STX occurs at an external superficial receptor near the Na+ channel and that the toxin affinity of the receptor may be modulated by fast Na+ activation and slow inactivation gating processes.

Animals↗
PubMed1983

Reactive glial protein synthesis and early disappearance of saxitoxin binding in degenerating rat optic nerve.

The biochemistry of gliotic CNS tissue was assessed by monotoring changes in de novo protein synthesis distal to site of crush in the rat optic nerve between 3 and 20 days post-operatively. Radioactivity profiles on 12% polyacrylamide SDS gels showed reproducible peaks associated with protein(s) with dissociated molecular weights of 57K, 51K, 42K, 40K, 37K and 23K. Differences between crush and control nerves were observed with respect to the latter two peaks. De novo synthesis of 23K protein (comigrant with myelin proteolipid protein) was evident in control but not crushed nerves. Synthesis of 37K protein (identity unknown) was evident at 7, 10 and (to a lesser extent) 20 days post-operatively in crushed nerves, but not in crushed nerves at 3 days post-operatively or in unoperated nerves at any time point. The appearance of the synthesis of the 37K protein coincides with a drop in the level of functional axolemma (assessed by [3H]saxitoxin binding) in crushed nerves from 78% to 36% of control levels between 3 and 7 days post-operatively.

Animals↗
PubMed1990

Voltage-dependent sodium channels in synaptoneurosomes: studies with 22Na+ influx and [3H]saxitoxin and [3H]batrachotoxinin-A 20-alpha-benzoate binding. Effects of proparacaine isothiocyanate.

22Na+ influx and binding of [3H]saxitoxin ([3H]STX) and [3H]batrachotoxin-A 20-alpha-benzoate ([3H]BTX-B) were studied in guinea pig cerebral synaptoneurosomes. STX and tetrodotoxin (TTX) completely blocked the stimulation of sodium influx induced by 1 microM BTX. The IC50 values for STX and TTX closely matched the Ki values for inhibition of [3H]STX binding, suggesting that the sites labelled by [3H]STX are associated with a population of BTX-sensitive channels. BTX induced a dose-dependent stimulation of sodium influx in synaptoneurosomes (EC50 280 nM). The potency of BTX for stimulation of sodium influx was increased (EC50 24 nM) in the presence of 0.6 microgram/ml scorpion venom without any change in maximal influx. In contrast, specific binding of [3H]BTX-B to synaptoneurosomes was minimal in the absence of scorpion venom, but it was increased several fold in the presence of 60 micrograms/ml scorpion venom. With proparacaine isothiocyanate (PROPRIT), an irreversible local anesthetic, the inhibition of [3H]BTX-B binding by PROPRIT did not occur in parallel with an inhibition of sodium influx induced by BTX. Preincubation of synaptoneurosomes with 10 microM PROPRIT for 10 min resulted in approximately 70% inhibition of [3H]BTX-B binding in the presence of scorpion venom. Such preincubation did not alter BTX-induced sodium uptake in synaptoneurosomes. Preincubations of synaptoneurosomes with 100 microM PROPRIT for 10 min completely inhibited [3H]BTX-B binding, and under these conditions BTX-induced sodium influx was reduced only by 50%. The results indicate that virtual elimination of binding sites labeled by [3H]BTX-B in the presence of scorpion venom by PROPRIT has little effect on sodium influx induced by BTX.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphibian Proteins↗
PubMed1990

Saxitoxin-sensitive Na+ channels: presynaptic localization in cerebellum and hippocampus of neurological mutant mice.

The autoradiographic distribution of saxitoxin (STX) binding sites associated with voltage-sensitive Na+ channel was studied in the cerebellum of neurological weaver (wv/wv), Purkinje cell degeneration (pcd/pcd), nervous (nr/nr) and reeler (rl/rl) mutant mice. The Purkinje cell layer contains the highest density of STX binding sites in normal mice. High densities were observed in the molecular layer. Intermediate and very low densities were present in the granular layer and the white matter respectively. There was an important decrease of grain density in the molecular layer and Purkinje cell layer of wv/wv cerebellum, where a large majority of granular cells had disappeared. In pcd/pcd and nr/nr mutants, a small decrease was observed in Purkinje cell layer where the Purkinje cells had almost all degenerated. In rl/rl mutants where all neuronal cells were malpositioned, the compacted molecular layer contained an increased STX binding sites density. Conversely the labelling of Purkinje cells areas was decreased. The hippocampal formation of rl/rl mutants presents an homogeneous repartition of the Na+ channel protein in contrast with the laminated distribution observed in normal mice. Our autoradiographic data suggest that a major proportion of STX-sensitive Na+ channels are localized in parallel fibers of granular cells and in axons of basket cells in a presynaptic position. In Purkinje cells, the dendritic arborization seems to be devoid of STX binding sites conversely to somata.

Animals↗
PubMed1989

A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II.

A single point mutation of the rat sodium channel II reduces its sensitivity to tetrodotoxin and saxitoxin by more than three orders of magnitude. The mutation replaces glutamic acid 387 with a glutamine and has only slight effects on the macroscopic current properties, as measured under voltage-clamp in Xenopus oocytes injected with the corresponding cDNA-derived mRNA.

Amino Acid Sequence↗
PubMed1991

Mapping the site of block by tetrodotoxin and saxitoxin of sodium channel II.

The SS2 and adjacent regions of the 4 internal repeats of sodium channel II were subjected to single mutations involving, mainly, charged amino acid residues. These sodium channel mutants, expressed in Xenopus oocytes by microinjection of cDNA-derived mRNAs, were tested for sensitivity to tetrodotoxin and saxitoxin and for single-channel conductance. The results obtained show that mutations involving 2 clusters of predominantly negatively charged residues, located at equivalent positions in the SS2 segment of the 4 repeats, strongly reduce toxin sensitivity, whereas mutations of adjacent residues exert much smaller or no effects. This suggests that the 2 clusters of residues, probably forming ring structures, take part in the extracellular mouth and/or the pore wall of the sodium channel. This view is further supported by our finding that all mutations reducing net negative charge in these amino acid clusters cause a marked decrease in single-channel conductance.

Action Potentials↗
PubMed1983

Occurrence of saxitoxin and other toxins in the liver of the pufferfish Takifugu pardalis.

Highly toxic livers of the pufferfish Takifugu pardalis were extracted with acidic ethanol. The toxins extracted were partially purified by chromatography on Bio-Gel P-2 and then Bio-Rex 70, resulting in separation into three fractions I, II and III. ratios of total mouse units per fraction were approximately 0.1:100:0.01, respectively, with tetrodotoxin (TTX) as standard. By TLC, electrophoresis and a TTX analyzer, Fr. II was identified as TTX and, unexpectedly, Fr. III as saxitoxin, while Fr. I remains unidentified.

Animals↗
PubMed1986

Pharmacological identification of saxitoxin-like toxins in the cultured purple clam, Hiatula diphos.

An outbreak of poisoning from ingestion of purple clam (Hiatula diphos), obtained from a brackish fish-culture pond, occurred in southern Taiwan in early January 1986. The extract blocked the twitch responses and generation of the action potential of the mouse diaphragm without an effect on the resting membrane potential or the miniature endplate potential. The depolarizations and spontaneous firings of the diaphragm induced by veratridine and crotamine were effectively antagonized by the toxic clam extract, indicating the presence of saxitoxin-like substances, which may have amounted to 0.013% tetrodotoxin equivalent.

Animals↗
PubMed1988

A tissue culture assay for tetrodotoxin, saxitoxin and related toxins.

In the presence of ouabain, veratridine enhances sodium influx in the mouse neuroblastoma cell line Neuro-2A (ATCC, CCL131), causing cellular swelling and subsequent death. Tetrodotoxin (puffer fish toxin) or saxitoxin (paralytic shellfish poison), both of which block the sodium channel of excitable membranes, antagonize this effect, enabling cell growth to continue. This phenomenon was used as the basis of a new assay for these toxins. It is also possible to estimate the quantity of TTX from the relationship between TTX concentration and percentage of living cells. This new method is simple, inexpensive, and sensitive, and may replace the conventional mouse bioassay.

Animals↗
PubMed1990

Presence of saxitoxin in toxic extracts from Gonyaulax polyedra.

A "red tide" bloom of Gonyaulax polyedra occurred in Italy in Autumn, 1988. Algal concentrated extracts and undiluted water samples from the bloom were tested both with the Microtox system and a mouse bioassay, revealing the presence of paralytic shellfish poison-like neurotoxins. Saxitoxin levels evaluated on the basis of toxicological and instrumental analysis showed discrepancies. Other toxins could be present in addition to paralytic shellfish poison.

Animals↗
PubMed1991

Protection against tetrodotoxin and saxitoxin intoxication by a cross-protective rabbit anti-tetrodotoxin antiserum.

A tetrodotoxin-formaldehyde-keyhole limpet hemocyanin conjugate was used to immunize a rabbit for the production of anti-toxin antiserum. The antiserum cross-reacted against both tetrodotoxin (TTX) and saxitoxin (STX), and in a quantitative in vitro assay was able to protect cells in a dose-dependent manner from the effects of either TTX or STX. The antiserum was also able to passively protect mice challenged in vivo with either toxin. Hybridomas producing monoclonal antibodies against toxin were obtained from the spleens of mice immunized with the same conjugate.

Animals↗
PubMed1993

Central and peripheral cardio-respiratory effects of saxitoxin (STX) in urethane-anesthetized guinea-pigs.

Effects of saxitoxin (STX; 10 micrograms/kg; i.p.) on cardio-respiratory activities were evaluated in urethane-anesthetized guinea-pigs. Concurrent recordings were made of electrocorticogram (ECoG), bulbar respiratory-related unit activities, diaphragmatic electromyogram (DEMG), electrocardiogram (Lead II ECG), blood pressure, heart rate, end-tidal CO2, arterial O2/CO2 tensions, and arterial pH. The average time to STX-induced respiratory failure was about 10 min. The most striking effect prior to apnea was a state of progressive bradypnea which emerged 5-7 min after the toxin administration. Other noteworthy responses included (i) a time-dependent decrease in ECoG amplitudes which typically began before the development of a bradypneic profile; (ii) an increasing degree of diaphragm neuromuscular blockade; (iii) a state of combined hypercapnia and uncompensated acidemia; (iv) a declining blood pressure; (v) an incrementally dysfunctional myocardial performance; and (vi) an increasingly degenerative central respiratory activity profile which ultimately culminated in a complete loss of central respiratory drive. The therapeutic effect of intratracheally administered oxygen was equivocal in that the cardio-respiratory activities, be they of central of peripheral nature, remained conspicuously dysfunctional and precarious despite 100% oxygen ventilation. What can be inferred from this study is two-fold. First, STX-induced ventilatory insufficiency can be attributed to a loss of functional integrity of both central and peripheral respiratory system components. That is, although diaphragm blockade contributes significantly to STX-induced respiratory failure, analyses of single respiratory unit activity data revealed that the central respiratory rhythmogenic mechanism also appeared to play a pivotal role in the development of a bradypneic profile which promotes, and directly causes, a complete loss of respiratory drive. Second, a state of unabating depression of central respiratory activities, which seemed to be refractory to the effect of O2, suggests STX has a direct and persistent action on medullary rhythmogenic mechanisms. In conclusion, these findings indicate that both central and peripheral cardio-respiratory components are critically involved in STX-induced apnea, dysfunctional cardiovascular performance, and lethality.

Anesthesia↗