Presynaptic toxins

Hawgood, B., Bon, C. (1991). Snake venom presynaptic toxins. In Handbook of Natural Toxins (A.T. Tu, ed.), Vol. 5, Reptile Venoms and Toxins, pp. 3-52. Marcel Dekker, New York. 

Presynaptic toxins - polypeptide snake venoms This group contains multimeric polypeptides containing subunits with phospholipase Aj activity, and often contains other subunits with a chaperone role. Toxicity does not normally rest on enzyme activity alone, and binding may occur other than on neuronal tissue, e.g. some cause skeletal muscle cytotoxicity. Examples from snake and viper venoms include agkistrodotoxin, ammodytoxin A. P-bungarotoxins. mojave toxin, notexin. taipoxin and textilotoxin. 

Presynaptic toxins - polypeptide insect venoms. A phospholipase Az venom is elaborated by the honey bee. 

There are several types of presynaptic toxins. They are structurally distinct among themselves. However, there is one common property, and that is the possession of phospholipase A activity. Phospholipase A is one of the common enzymes found in various snake venoms and animal tissues. However, not all phospholipases A are toxic. The toxic phospholipase A is usually a basic protein. There is as yet no satisfactory explanation for this. Tsai et al. (1987) found that the basic amino acids tended to cluster near the surface region at the NH2-terminal side in basic phospholipase A. This may have something to do with toxicity. 

One type of presynaptic toxin is composed of two subunits bound together. The basic subunit has phospholipase A activity, whereas the acidic subunit has no enzymic activity. Crotoxin is the first presynaptic toxin isolated from snake venom and is also one of the most well-studied presynaptic toxins. 

The role of the acidic subunit A is to guide the toxin to a specific site, then the basic subunit B functions as a presynaptic toxin (Hendon and Tu, 1979). Each subunit alone is relatively nontoxic, but combined, the toxicity is greatly enhanced (Trivedi et al., 1989). The undissociated crotoxin itself shows phospholipase A activity, indicating the active site of subunit B is not masked by subunit A (Radvanyi and Bon, 1984). Besides neurotoxicity, subunit B also has hemolytic activity. Subunit B attaches to many parts of the erythrocyte membranes (Jeng et al., 1978) and also on the postsynaptic membrane (Bon et al., 1979), in addition to the presynaptic binding site. 

The acidic and basic subunit types presynaptic toxins are fairly common in neurotoxic snake venoms. For instance, such toxins have been isolated from the venoms of C. viridis concolor (Aird et al., 1989b) and C. durissus collilineatus (Lennon and Kaiser, 1990). The... 

Although most studies of presynaptic toxins are focused on the nerve ending of the neuromuscular junction or synasptosomes, the toxin may have broader biological action. For instance, Mojave toxin inhibits calcium channel dihydropyridine receptor binding in rat brain (Valdes et al., 1989). 

Because the action of a presynaptic toxin, P-btx, is to start the initial burst of acetylcholine followed by the stop of acetylcholine release, it eventually causes paralysis of the muscle. The mechanism does not involve the hydrolysis of acetylcholine therefore, it is reasonable that anticholinesterase does not overcome p-btx s effect. 

The third type of presynaptic toxin is a tertiary complex of three polypeptide chains. Taipoxin from the venom of the Australian snake, taipan, has three subunits, a, p, and y, with an Mr of46,000. The number of amino acid residues present in the subunits is 120, 120, and 135, respectively. The a-chain is basic and has phospholipase A activity. 

From all the presynaptic toxins examined, one sees that they possess phospholipase A activity but the reverse is not true. There are many proteins with phospholipase A activity, and not all of them are toxic only those with basic phospholipase A are toxic, and only some of them are presynaptic neurotoxins. 

Not every presynaptic toxin is identical in relation to the release of acetylcholine from the presynaptic site. With P-btx, there is an initial burst of acetylcholine, but eventually the release is stopped. Even though toxins may behave like P-btx, the length of time for acetylcholine release is different for each toxin. Some presynaptic toxins do not release acetylcholine from the beginning and simply stop the release. In such an event, the depolarization wave never reaches the muscle, and the muscle is paralyzed. 

The enzyme itself will cause mild myonecrosis, and the necrotic activity can be greatly enhanced by the addition of phosphatidylcholine. Apparently phospholipase A2 itself is an indirect agent, producing lysophosphatidylcholine, which is the direct agent. Phospholipase A2 itself can be separated from the main toxic fraction however, many presynaptic toxins such as p-bungarotoxin and notexin have weak phospholipase A2 activity. 

Hawgood, B., and Bon, C. (1991). Snake venom presynaptic toxins. Handbook Natural Toxins 5 3-52. 

Tetanus is a disease caused by the release of neurotoxins from the anaerobic, spore-forming rod Clostridium tetani. The clostridial protein, tetanus toxin, possesses a protease activity which selectively degrades the pre-synaptic vesicle protein synaptobrevin, resulting in a block of glycine and y-aminobutyric acid (GABA) release from presynaptic terminals. Consistent with the loss of neurogenic motor inhibition, symptoms of tetanus include muscular rigidity and hyperreflexia. The clinical course is characterized by increased muscle tone and spasms, which first affect the masseter muscle and the muscles of the throat, neck and shoulders. Death occurs by respiratory failure or heart failure. 

While most investigations show that sea snake neurotoxins are postsynaptic type, Gawade and Gaitonde (23) stated that Enhydrina schistosa major toxin has dual actions or postsynaptic as well as presynaptic toxicity. E, schistosa venom phospholipase A is both neurotoxic and myotoxic. Neurotoxic action of the enzyme is weak so that there is sufficient time for myonecrotic action to take place (24), Sea snake, L. semifasciata toxin also inhibits transmission in autonomic ganglia, but has no effect on transmission in choroid neurons. 

Bacterial botulinum toxin blocks presynaptic acetylcholine release 725 Snake, scorpion, spider, fish and snail peptide venoms act on multiple molecular targets at the neuromuscular junction 727 Electrolyte imbalances alter the voltage sensitivity of muscle ion channels 728... 

All botulin neurotoxins act in a similar way. They only differ in the amino-acid sequence of some protein parts (Prabakaran et al., 2001). Botulism symptoms are provoked both by oral ingestion and parenteral injection. Botulin toxin is not inactivated by enzymes present in the gastrointestinal tracts. Foodborne BoNT penetrates the intestinal barrier, presumably due to transcytosis. It is then transported to neuromuscular junctions within the bloodstream and blocks the secretion of the neurotransmitter acetylcholine. This results in muscle limpness and palsy caused by selective hydrolysis of soluble A-ethylmalemide-sensitive factor activating (SNARE) proteins which participate in fusion of synaptic vesicles with presynaptic plasma membrane. SNARE proteins include vesicle-associated membrane protein (VAMP), synaptobrevin, syntaxin, and synaptosomal associated protein of 25 kDa (SNAP-25). Their degradation is responsible for neuromuscular palsy due to blocks in acetylcholine transmission from synaptic terminals. In humans, palsy caused by BoNT/A lasts four to six months. 

Acetylcholine release is inhibited by one of the most potent toxins, the botulims toxin produced by the anaerobic bacterium Clostridium botulinum. The toxin, lethal at 1 ng/kg in humans, enters the synapse by endocytosis at nonmyelinated synaptic membranes and produces muscle paralysis by blocking the active zone of the presynaptic membrane... 

Schematic illustration of a generalized cholinergic junction (not to scale). Choline is transported into the presynaptic nerve terminal by a sodium-dependent choline transporter (CHT). This transporter can be inhibited by hemicholinium drugs. In the cytoplasm, acetylcholine is synthesized from choline and acetyl -A (AcCoA) by the enzyme choline acetyltransferase (ChAT). Acetylcholine is then transported into the storage vesicle by a second carrier, the vesicle-associated transporter (VAT), which can be inhibited by vesamicol. Peptides (P), adenosine triphosphate (ATP), and proteoglycan are also stored in the vesicle. Release of transmitter occurs when voltage-sensitive calcium channels in the terminal membrane are opened, allowing an influx of calcium. The resulting increase in intracellular calcium causes fusion of vesicles with the surface membrane and exocytotic expulsion of acetylcholine and cotransmitters into the junctional cleft (see text). This step can he blocked by botulinum toxin. Acetylcholine s action is terminated by metabolism by the enzyme acetylcholinesterase. Receptors on the presynaptic nerve ending modulate transmitter release. SNAPs, synaptosome-associated proteins VAMPs, vesicle-associated membrane proteins.

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