Neurotoxins sodium channels

Mode of Action. DDT and its analogues specifically affect the peripheral sense organs of insects and produce violent trains of afferent impulses that result in hyperactivity, convulsions, and paralysis. Death results from metaboHc exhaustion and the production of an endogenous neurotoxin. The very high lipophilic nature of these compounds faciUtates absorption through the insect cuticle and penetration to the nerve tissue. The specific site of action is thought to be the sodium channels of the axon, through inhibition of Ca " ATPase. 

Sensitive to toxins, in this case means that the assay presents no false negative results. Primary hepatocytes can elucidate hepatotoxins, and mouse neuroblastoma cells can elucidate sodium channel-blocking neurotoxins therefore these assays can be used to screen for the appropriate toxins. 

Turning now to chemical attack, many predators immobilize their prey by injecting toxins, often neurotoxins, into them. Examples include venomous snakes, spiders, and scorpions. Some spider toxins (Quick and Usherwood 1990 Figure 1.3) are neurotoxic through antagonistic action upon glutamate receptors. The venom of some scorpions contains polypeptide neurotoxins that bind to the sodium channel. 

The tetrodotoxins (TTXs) and saxitoxins (STXs) have in common the ability to block sodium channels of excitable membranes (1—5), Saxitoxin and tetrodotoxin are some of the most potent non-proteinaceous neurotoxins known and are responsible for significant human morbidity and mortality (6, 7). Although for many years the biosynthetic origin(s) of TTXs and STXs has not been identified, recent evidence indicates that bacteria may be a source. 

Research in this area advanced in the 1970 s as several groups reported the isolation of potent toxins from P. brevis cell cultures (2-7). To date, the structures of at least eight active neurotoxins have been elucidated (PbTx-1 through PbTx-8) (8). Early studies of toxic fractions indicated diverse pathophysiological effects in vivo as well as in a number of nerve and muscle tissue preparations (reviewed in 9-11). The site of action of two major brevetoxins, PbTx-2 and PbTx-3, has been shown to be the voltage-sensitive sodium channel (8,12). These compounds bind to a specific receptor site on the channel complex where they cause persistent activation, increased Na flux, and subsequent depolarization of excitable cells at resting... 

Alteromonas species producing sodium channel blockers, 80r,82 Anabaena flos-aquae neurotoxins, 88 toxic principle, 108 Analyses, definition, 43 Anatoxin(s) isolation, 88 types, 88,91 Anatoxin a... 

Very rapid-acting paralytic neurotoxin that binds to sodium channels of nerve and muscle cells depolarizing neurons by increasing the sodium channel permeability. It is obtained from South American poison-dart frogs (Phyllobates aurotaenia, Phyllobates terribilis). It is insoluble in water but soluble in hydrocarbons and other nonpolar solvents. The dried toxin can remain active for at least a year. However, it is relatively nonpersistent in the environment. 

Paralytic neurotoxins that bind to sodium channels of nerve and muscle cells causing muscle contractions. They are obtained from the dinoflagellate that causes "red-tide" (Gymnodinium breve). Toxins are typically light tan crystalline solids. They are insoluble in water and very unstable. 

Rapid-acting paralytic neurotoxins that blocks transient sodium channels and inhibits depolarization of nerve cells. They are some of the causative agents of paralytic shellfish poisoning (PSP). They are obtained from dinoflagellates (Gonyaulax spp., Alexandrium spp.) and cyanobacteria (Anabaena circinalis). 

Rapid-acting neurotoxin that binds to sodium channels in nerve tissue leading to an increase in the release of neurotransmitters. It is a solid obtained from the venom of the Brazilian scorpion Tityus serrulatus. 

Neurotoxin that preferentially binds to activated sodium channels and increases the intracellular calcium concentration. It prolongs the action potential duration in the heart. It is obtained from sabadilla seeds (Schoenocaulon officinale). Yellowish-white amorphous powder that retains water and melts at 356°F. It is insoluble in water but slightly soluble in ether. Various salts (solids) have been reported. The nitrate is sparingly soluble in water. 

Catterall, W. A. Neurotoxins acting on sodium channels. Annu. Rev. Pharmacol. Toxicol. 20,15-43,1980. 

Trainer VL, Moreau E, Guedin D, Baden DG, Catterall WA (1993) Neurotoxin binding and allosteric modulation at receptor sites 2 and 5 on purified and reconstituted rat brain sodium channels. JBiol Chem 268 17114—17119... 

Neurotoxins, such as saxitoxin and anatoxin-a, have been implicated in mediating competitive interactions between toxic cyanobacteria and other photoautotrophs, but few studies have explicitly examined the allelopathic effects of these compounds (e g., Kearns and Hunter 2001). Although it is reasonable to assume that these compounds bind to algal and cyanobacterial sodium channels in a similar fashion as in vertebrate neurons, support for this hypothesis is currently lacking. 

The ditetrazolium salts (309) have been patented for use in electrochromic electrodes which are used in display devices <89JAP01230026) and tetrazolium salts have also been developed for cell bioassays for neurotoxins active on voltage-sensitive sodium channels <93MI 417-03). Tests for inhibition of corrosion of zinc and brass carried out on 5-aminotetrazole showed it to be ineffective relative to other azoles <86MI 417-01). A number of tetrazoles including the 5-amino, 5-methyl, and 5-phenyl derivatives have been separately incorporated into surfactants used for corrosion inhibition with copper in water <9lMl4l7-07). Photopolymerizable resin compositions which are highly resistant... 

It is also interesting that in ATX la, which is a potent crustacean neurotoxin but a poor mammalian cardiac stimulant, Lys37 and both histidines are missing, suggesting that one or more of these side chains may be important in promoting specificity for the mammalian cardiac sodium channel. 

Wang SY, Wang GK. Voltage-gated sodium channels as primary targets of diverse lipid-soluble neurotoxins. Cell Signal. 2003 15 151-159. 

Aconites, commonly called wolfsbane or monkshood, are species of Aconitum (Ranunculaceae), valued ornamental herbaceous plants, grown for their showy blue or purple flowers, which are shaped like a monk s cowl. Their alkaloid content, mainly in the roots, makes them some of the most toxic plants commonly encountered. The dried roots of Aconitum napellus were once used, mainly externally for relief of pain, e.g. in rheumatism. The toxic alkaloids (0.3-1.5%) are complex diterpene-derived esters. Aconitine (Figure 6.124) is the principal component (about 30%) and is a diester of aconine with acetic and benzoic acids. Hydrolysis products benzoylaconine and aconine are also present in dried plant material. These alkaloids appear to behave as neurotoxins by acting on sodium channels. All species of Aconitum and Delphinium are potentially toxic to man and animals and must be treated with caution. 

Cestele S, Catterall WA (2000) Molecular mechanisms of neurotoxin action on voltage-gated sodium channels. Biochimie 82 883-892... 

Saxitoxin (32) is listed in Schedule 1 of the CWC. It is a polar, cationic, relatively low molecular mass toxin and is one of 18 structurally related neurotoxins collectively known as paralytic shellfish poisoning (PSP) toxins. Analogues are formed by addition of sulfate, A-sulfo and A-hydroxyl groups, and by decarbamylation. They block neuronal sodium channels, and thereby neurotransmission, death resulting from respiratory paralysis. Saxitoxin is produced by dinoflagellate species (and by some freshwater cyanobacteria), and accumulates in shellfish. The cationic nature of saxitoxin makes capillary electrophoresis combined with... 

The neurotoxins TTX and STX bind with similar affinity to all conformational states. Most other small molecule sodium channel blockers appear to interact preferentially with the open state, an inactivated state, or a combination of open and inactivated states. Since channel residence in these states is controlled by membrane voltage, state-dependent sodium channel blockers show both voltage- and use-dependence, i.e., their potency increases with more depolarized holding potentials and higher frequency stimulation [8-10]. 

Sodium channels are associated with a rich pharmacology, including the potent neurotoxins TTX and STX, as well as numerous clinically used therapeutic agents. TTX and STX bind with similar affinity to all conformational states and prevent sodium permeation by physically occluding the pore [45,46]. Most other non-peptide sodium channel blockers appear to interact preferen-... 

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