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PubMed1978

Binding to saxitoxin to electrically excitable neuroblastoma cells.

Saxitoxin inhibits the action potential Na+ ionophore of electrically excitable neuroblastoma cells with a KI of 3.7 nM. Binding experiments detect a single class of saturable binding sites with KD = 3.9 nM and a binding capacity of 156 fmol/mg of cell protein (78 sites per micrometer2 of cell surface). Saturable binding is completely inhibited by tetrodotoxin but is unaffected by scorpion toxin or batrachotoxin. No saturable binding is observed in cultures of clone N103, a variant neuroblastoma clone lacking the action potential Na+ response. Thus, saxitoxin binds specifically to the action potential Na+ ionophore in neuroblastoma cells. Comparison of saxitoxin and scorpion toxin binding reveals that there are three saxitoxin receptor sites for each scorpion toxin receptors site. The implications of this stoichiometry are considered.

Action Potentials↗

PubMed1980

Purification from rat sarcolemma of the saxitoxin-binding component of the excitable membrane sodium channel.

The saxitoxin-binding component (SBC) of the excitable membrane sodium channel has been solubilized and purified from rat skeletal muscle sarcolemma. Phospholipid was required in mixed micelles with detergent for stability of the mammalian SBC. Even at optimal detergent-to-phospholipid ratio, the solubilized SBC showed significant temperature-dependent loss of specific toxin binding with time, necessitating maintenance of low temperatures during purification. Characteristics of saxitoxin binding to the solubilized material closely resembled those seen in intact membranes. A weak anion-exchange column was synthesized; it provided rapid 10- to 20-fold purification of the solubilized SBC. Additional necessary purification was obtained by chromatography on immobilized wheat germ agglutinin. Specific saxitoxin-binding activity of the purified material averaged approximately 1500 pmol of saxitoxin bound per mg of protein. Three bands were present in this material on sodium dodecyl sulfate/polyacrylamide gel electrophoresis. The purified material sedimented on a sucrose gradient with an apparent s20,w of 9.9 S.

Animals↗

PubMed1982

Isolation and characterization of a monoclonal antibody against the saxitoxin-binding component from the electric organ of the eel Electrophorus electricus.

A monoclonal hybridoma cell line secreting antibody against the saxitoxin-binding component from the eel Electrophorus electricus has been isolated. The specificity of this monoclonal antibody was established by (i) its ability to immunoprecipitate bound [3H]saxitoxin from a detergent extract of electroplax membranes in a dose-dependent manner, (ii) the inability of unrelated monoclonal antibodies to immunoprecipitate the toxin-binding activity in a similar assay, and (iii) the ability of excess unlabeled tetrodotoxin to displace [3H]saxitoxin from the immunoprecipitated component. The antibody is of the subclass IgG1 and binds specifically to a polypeptide component of Mr approximately 250,000 on NaDodSO4/polyacrylamide gels. The antigenic determinant is associated with the same polypeptide component throughout the purification procedure, indicating that this component is not a result of artifactual aggregation or degradation during isolation. We conclude that the 250,000-dalton polypeptide is part of the saxitoxin binding/sodium channel protein in the native electroplax membrane.

Animals↗

PubMed1986

Discrimination of muscle and neuronal Na-channel subtypes by binding competition between [3H]saxitoxin and mu-conotoxins.

The effect of two mu-conotoxin peptides on the specific binding of [3H]saxitoxin was examined in isolated plasma membranes of various excitable tissues. mu-Conotoxins GIIIA and GIIIB inhibit [3H]saxitoxin binding in Electrophorus electric organ membranes with similar KdS of approximately equal to 50 X 10(-9) M in a manner consistent with direct competition for a common binding site. GIIIA and GIIIB similarly compete with the majority (80-95%) of [3H]saxitoxin binding sites in rat skeletal muscle with KdS of approximately 25 and approximately 140 X 10(-9) M, respectively. However, the high-affinity saxitoxin sites in lobster axons, rat brain, and rat heart are virtually insensitive to GIIIA concentrations up to 10 microM. These results and previously published data suggest that three Na-channel subtypes can be distinguished on the basis of toxin pharmacology: Na channels of skeletal muscle and Electrophorus electroplax have high affinity for mu-conotoxins and tetrodotoxin, neuronal Na channels have low affinity for mu-conotoxins and high affinity for tetrodotoxin, while heart Na channels and a similar subtype also found in denervated muscle have low affinity for both mu-conotoxin and tetrodotoxin.

Animals↗

PubMedDate not supplied

Do saxitoxin-like substances have a role in scombrotoxicosis?

Evidence is presented which establishes that mackerel fed in captivity can, by relay from contaminated shellfish via sand eels, accumulate paralytic shellfish poisons (PSP) in the edible flesh at a level (250 micrograms saxitoxin equivalents per kg) similar to that in the contaminated shellfish. Data from ELISAs performed independently in two laboratories show that commercial mackerel fillets which have been associated with incidents of scombrotoxicosis contained 0.02-1.30 micrograms saxitoxin equivalents per kg, concentrations some two to four orders of magnitude below that normally detectable by the mouse bioassay. The doses, expressed as saxitoxin equivalents, administered inadvertently during volunteer testing of such fillets ranged up to 0.5 ng/kg bw, at least four orders of magnitude less than the fatal oral dose for an adult. The doses associated with the rapid induction of nausea/vomiting and/or diarrhoea, 0.11-1.0 ng/kg bw, could not be distinguished from the doses which failed to produce such symptoms in susceptible volunteers (up to 0.5 ng/kg bw). Factors that might explain this lack of correlation between dose (saxitoxin equivalents) and volunteer response are discussed along with previously published reports of PSP relay through the food web. It is suggested that the relay of algal toxins, particularly PSP, but possibly in combination with diarrheic shellfish poisons, may be responsible for scombrotoxicosis.

Animals↗

PubMed2003

Chlorination for degrading saxitoxins (paralytic shellfish poisons) in water.

Chlorination was investigated as a treatment option for degrading and thus removing saxitoxins (paralytic shellfish poisons, PSPs) produced by cyanobacteria (blue-green algae) from water. It was found to be effective with the order of ease of degradation of the saxitoxins being GTX5 (B1) approximately dcSTX > STX > GTX3 approximately C2 > C1 > GTX2. However the effectiveness of chlorine was pH dependent. Degradation as a function of pH was not linear with the degree of degradation increasing rapidly at around pH 7.5. At pH 9 > 90% removal was possible provided a residual of 0.5 mg l(-1) free chlorine was present after 30 min contact time. The more effective degradation at higher pH was unexpected as chlorine is known to be a weaker oxidant under these conditions. The more effective degradation, then, must be due to the toxins, which are ionisable molecules, being present in a form at higher pH which is more susceptible to oxidation. The feasibility of using chlorine to remove saxitoxins during water treatment will therefore depend strongly on the pH of the water being chlorinated. Degradation may be improved by pH adjustment but may not be a practical solution. Although saxitoxins were degraded in that the parent compounds were not detected by chemical analysis, there is no indication as to the nature of the degradation products. However, acute toxicity as determined by the mouse bioassay was eliminated.

Animals↗

PubMed1979

Pharmacological properties of axonal sodium channels in the cockroach Periplaneta americana L. I. Selective block by synthetic saxitoxin.

Voltage-clamp experiments on isolated giant axons of the cockroach Periplaneta americana L. show that chemically synthesized saxitoxin specifically and reversibly blocks the transient inward sodium current without affecting the steady-state outward potassium current. From the concentration depending of sodium current suppression it is concluded that individual sodium channels are blocked by single molecules of synthetic saxitoxin which bind reversibly to part of the channel with a dissociation constant of 3.0 x 10(-9) M. Synthetic saxitoxin blocks sodium channels in cockroach axons at a lower concentration than tetrodotoxin. Sodium channel block by synthetic saxitoxin is more readily reversed than tetrodotoxin-induced block.

Animals↗

PubMed1986

The tip-E mutation of Drosophila decreases saxitoxin binding and interacts with other mutations affecting nerve membrane excitability.

A recessive temperature-sensitive paralytic mutation, tip-E, is associated with reduced binding of [3H]saxitoxin to voltage-sensitive sodium channels in membranes from adult Drosophila heads. There is a decrease of 30-40% in the number of [3H]saxitoxin-binding sites per mg protein (Bmax), but the dissociation constant (Kd) for [3H]saxitoxin binding is normal in the remaining population of binding sites. This decrease is not due to a general hypotrophy of neural tissue since the number of alpha-bungarotoxin binding sites is normal in tip-E mutants. Although saxitoxin binding is reduced in vitro, pharmacological experiments suggest that tip-E mutants have close to the wild-type number of sodium channels in vivo. This suggestion is supported by the observation that at permissive temperatures tip-E only marginally suppresses a mutation which causes enhanced membrane excitability. However, even at permissive temperatures tip-E interacts synergistically with mutations that decrease membrane excitability. In this case, the double mutants exhibit reduced viability and/or longevity. We postulate that either the structure of sodium channels or their microenvironment is altered in tip-E mutants resulting in an increased liability of binding sites in vitro.

Amphibian Proteins↗

PubMed1967

Saxitoxin and tetrodotoxin: comparison of nerve blocking mechanism.

Saxitoxin at concentrations of 3 x 10(-8) to 3 x 10(-7) mole per liter blocks the conduction of lobster giant axon with no change in resting potential. Recovery of washed axons is faster in those that had been treated with saxitoxin than it is in those that were treated with tetrodotoxin. Peak transient increase in nerve membrane conductance is selectively blocked by saxitoxin with no change in late steady-state increase in conductance. The major mechanism of saxitoxin blockage is the same that of tetrodotoxin blockage.

Action Potentials↗

PubMed1979

Binding of radioactively labeled saxitoxin to the squid giant axon.

The binding of saxitoxin, a specific inhibitor of the sodium conductance in excitable membranes, has been measured in giant axons from the squid, Loligo pealei. Binding was studied by labeling saxitoxin with tritium, using a solvent-exchange technique, and measuring the toxin uptake by liquid scintillation counting. Total toxin binding is the sum of a saturable, hyperbolic binding component, with a dissociation constant at 2--4 degrees C of 4.3 +/- 1.7 nM (mean SE), and a linear, nonsaturable component. The density of saturable binding sites is 166 +/- 20.4 micrometers-2. From this density and published values of the maximum sodium conductance, the conductance per toxin site is estimated to be about 7 pS, assuming sequential activation and inactivation processes (F. Bezanilla & C.M. Armstrong, 1977, J. Gen. Physiol. 70:549). This single site conductance value of 7 pS is in close aggreement with estimates of the conductance of one open sodium channel from measurements of gating currents and of noise on squid giant axons and is consistent with the hypothesis that one saxitoxin molecule binds to one sodium channel.

Animals↗

PubMed2005

An ab initio study of the guanidinium groups in saxitoxin.

Quantum chemical (Hartree-Fock) calculations were performed on neutral and protonated saxitoxin in order to obtain optimum geometries, rotational energy barriers for the guanidinium ions and proton affinities. For comparison purposes, as model compounds, guanidinium systems in five and six membered rings were also investigated. In addition, DFT (B3LYP) calculations with the 6-31G** basis set were performed and the sodium affinities of the guanidinium groups in saxitoxin were obtained. It was concluded that the inhibition of the sodium channels by the saxitoxin is due to the interaction of the guanidinium group with carboxylate groups from the wall of the channel and not to the binding of the sodium ions.

Guanidine↗

PubMed1980

Size characteristics of the solubilized sodium channel saxitoxin binding site from mammalian sarcolemma.

The sodium channel saxitoxin binding component from rat sarcolemma was solubilized with medium chain length non-ionic detergents including NP-40, Brij-96 and Lubrol-PX. Phospholipid was required for stability of the binding component. Specific saxitoxin binding was significantly temperature sensitive even with optimal levels of phospholipid present. The solubilized saxitoxin binding component chromatographed on Sepharose 6B at a position corresponding to that of a globular protein of 95--10 A Stokes radius, but had an apparent s20,w typical of a smaller molecule (s20,w = 9.2--10). Column behavior and s20,w were independent of the specific detergent used for solubilization. Anomalous column behavior may reflect molecular asymmetry, contribution from bound detergent or similar considerations.

Animals↗

PubMed1984

Occurrence of saxitoxin in puffer fish.

Three species of puffer fish, Takifugu poecilonotus, T. vermicularis and T. radiatus, were examined for the presence of toxic components other than tetrodotoxin. Saxitoxin, a paralytic shellfish toxin, was found in the livers, ovaries and digestive tracts of the first two species but not in the last species. The puffers are assumed to accumulate saxitoxin by feeding on bivalves that have ingested a toxic dinoflagellate Protogonyaulax tamarensis. Another toxic component is present in the liver of T. poecilonotus, but its structural relationship to tetrodotoxin or saxitoxin is questionable.

Animals↗

PubMed1988

Appearance and partial purification of a high molecular weight protein in crabs exposed to saxitoxin.

This paper provides evidence for a protein component which appears to be involved in the seasonal resistance of small shore crabs, Hemigrapsus oregonesis and Hemigrapsus nudus to saxitoxin, a principle neurotoxin involved in paralytic shellfish poisoning (PSP). This unique protein complex was isolated and partially purified by ion exchange chromatography using DEAE-cellulose from visceral tissue extracts of resistant crabs. The complex was absent in control crabs that were sensitive to saxitoxin. In addition, the protein complex was induced in the crab after acute administration of low doses of saxitoxin. Results indicate that the protein complex is acidic in nature and has an apparent mol. wt of 145,000.

Animals↗

PubMed1989

Respiratory effects of brevetoxin and saxitoxin in awake guinea pigs.

Ptychodiscus brevis toxin (brevetoxin) is associated with 'Florida red tide' and cause neurotoxic shellfish poisoning. Saxitoxin is the agent of paralytic shellfish poisoning. Clinical reports of human intoxication suggest that both toxins affect the respiratory system. The toxins were administered by slow intravenous infusion. The effects of the toxins on respiratory function of awake guinea pigs in a pressure plethysmograph were studied. Both toxins caused lactic acidosis of unknown etiology, which was compensated for by increased minute volume with brevetoxin (PbTx-3)- but not with saxitoxin-intoxicated animals. In general, brevetoxin increased ventilation, before respiratory failure, while saxitoxin had a depressive effect on ventilation. Airways resistance was not increased, nor was dynamic compliance decreased during intoxication, although the data suggest that respiratory system failure was the primary cause of death. The responses seen in these experiments are consistent with the dissimilar molecular actions of these toxins.

Animals↗

PubMed1994

Development of a monoclonal-based enzyme-linked immunoassay for saxitoxin-induced protein.

A monoclonal antibody was generated against saxitoxin-induced protein (SIP) from the small shore crab Hemigrapsus oregenesis. SIP was induced by saxitoxin injection and could be detected in the crude crab extracts with both polyclonal and monoclonal antibody preparations. On Western blots, the polyclonal serum reacted against several bands which were induced by saxitoxin in the crude extracts. These bands represented proteins related to SIP. The monoclonal (4G5), however, was specific for the 79,000 mol. wt subunit of SIP. A triple antibody sandwich ELISA was developed in which polyclonal anti-SIP IgG was used as a trapping layer and monoclonal 4G5 was used as the detection layer. This assay was shown to be more specific and more accurate than a direct bind assay which employed the polyclonal antiserum alone. Although the polyclonal serum was more sensitive than the monoclonal on Western blots, the triple antibody sandwich and direct bind ELISAs were of comparable sensitivity.

Animals↗

PubMed2005

Selective detection of saxitoxin over tetrodotoxin using acridinylmethyl crown ether chemosensor.

At pH 7.1, saxitoxin decomposes to produce a trace impurity that can interfere with fluorescence sensing when using irradiation wavelengths near 325 nm. The fluorophore acridine is found to be a suitable component of arylmethyl crown ether chemosensors for the fluorescent detection of saxitoxin. These sensors are selective for the detection of saxitoxin over tetrodotoxin.

Biosensing Techniques↗

PubMed2002

Chemosensors for the marine toxin saxitoxin.

Eleven anthracylmethyl crown ethers have been synthesized and evaluated as fluorescence sensors for the marine toxin saxitoxin. Fluorescence enhancement data are consistent with a 1:1 binding complex for all crowns. The binding constants are in the range of 10(4) M(-)(1) in ammonium phosphate buffer (pH 7.1) in 80% ethanol solvent. Selectivity for sensing saxitoxin versus several organic analytes has been demonstrated for the first time. Possible modes of binding are presented, and relevance to saxitoxin monitoring programs are discussed.

Animals↗