Neurotoxins are toxins that are poisonous or destructive to nerve tissue (causing neurotoxicity). . Though diverse in chemical properties and functions, neurotoxins share the common property that they act by some mechanism leading to either. Acrolein acts as a neurotoxin in the nigrostriatal dopaminergic system of rat: involvement of α-synuclein aggregation and programmed cell. Toxins are potent molecules used by various bacteria to interact with a host organism. Some of them specifically act on neuronal cells (clostridial neurotoxins ).
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We have used immunohistochemistry and immunoblotting to demonstrate alterations in toxin substrates in intact neurons under conditions of toxin-induced blockade of neurotransmitter release.
Vesicle-associated membrane protein, which co-localizes with synaptophysin, is not detectable in tetanus toxin-blocked cultures. Syntaxin, also concentrated in synaptic sites, is cleaved by botulinum neurotoxin C. Similarly, the carboxyl terminus of the synaptosomal-associated protein of 25 kDa SNAP is not detectable in botulinum neurotoxin A-treated cultures.
Unexpectedly, tetanus toxin exposure causes an increase in SNAP immunofluorescence, reflecting increased accessibility of antibodies to antigenic sites rather than increased expression of the protein. Furthermore, botulinum neurotoxin C causes a marked loss of the carboxyl terminus of SNAP when the toxin is added to living cultures, whereas it has no action on SNAP in in vitro preparations. This study is the first to demonstrate in functioning neurons that the physiologic response to these toxins is correlated with the proteolysis of their respective substrates.
Furthermore, the data demonstrate that botulinum neurotoxin C, in addition to cleaving syntaxin, exerts a secondary effect on SNAP Clostridial neurotoxins CNTs 1 are synthesized as single polypeptides of kDa and subsequently are cleaved to active disulfide-linked dichain toxins. The heavy chain kDa carries the receptor binding and transmembrane domains of the toxin, and the light chain 50 kDa contains the catalytic domain that blocks neurotransmitter release 1 , 2.
Clostridial neurotoxins are zinc endopeptidases 3 , 4 , 5 , which cleave specific proteins thought to be involved in the synaptic vesicle docking-fusion complex. Two isoforms of VAMP in neuronal tissue and a nonneuronal homologue cellubrevin have been identified in a number of animal species 19 , 20 , 21 , VAMP is comprised of three major domains: Syntaxin has two isoforms that are anchored to membranes by a single COOH-terminal transmembrane domain 26 , Syntaxin binds to presynaptic calcium channels and to synaptotagmin located in the synaptic vesicle membrane 26 , 28 , Botulinum neurotoxin C cleaves syntaxin at a site near the transmembrane domain 13 , 14 , SNAP is a membrane-associated cytoplasmic protein implicated in the fusion of synaptic vesicles with the presynaptic membrane 15 and in membrane addition leading to constitutive axonal growth SNAP is a hydrophilic protein that is palmitylated at one to four of its closely spaced cysteine residues and acts as an integral membrane protein 32 , TeNT-induced disappearance of inhibitory and excitatory postsynaptic potentials coincides in the same system with the blockade of inhibitory and excitatory neurotransmitter release Mouse monoclonal antibody against synaptophysin was from Boehringer Mannheim.
Anti-VAMP antibodies were produced in rabbits to synthetic peptides corresponding to amino acids of the VAMP variable domain from each of the two isoforms found in rat brain and affinity purified using the synthetic peptides. Polyclonal antibodies were raised in rabbits against a peptide consisting of the COOH-terminal 12 amino acids of SNAP conjugated to keyhole limpet hemocyanin and affinity purified from columns containing the peptide coupled to Sepharose.
Antibodies specific for syntaxin were obtained by immunizing rabbits with recombinant syntaxin 1A and purifying the IgG fraction. Spinal cords from day fetal mice were dissociated and plated in mm Vitrogen- Collagen Corp. Spinal cord cultures were rinsed once in minimum essential medium and incubated for 20 h in 0.
The pH was adjusted to 7. To evoke neurotransmitter release, cultures were exposed sequentially to 1. HBSS without calcium and with 0. In a previous study, we demonstrated by thin-layer chromatography that virtually all of the radioactivity, [ 3 H]glycine or [ 3 H]glutamate, released under these conditions co-migrates with free glycine or free glutamate, respectively Cell-associated radioactivity was assayed after dissolving the cells in 0.
Calcium-dependent release was calculated as the amount of radiolabel released in the presence of calcium minus the amount released in the absence of calcium and normalized to the total radioactivity in the culture at the start of the release assay.
Control and toxin-treated 0. After incubation with toxins 0. Spinal cord cell cultures contain a heterogeneous population of neurons growing on a monolayer of nonneuronal cells Fig. Its implication in faster translocation. Binding and transcytosis of botulinum neurotoxin by polarized human carcinoma cells.
Structural features of the botulinum neurotoxin molecule that govern binding and transcytosis across polarized human intestinal epithelial cells. Visualization of binding and transcytosis of botulinum toxin by human intestinal epithelial cells.
Receptor-mediated transcytosis of botulinum neurotoxin A through intestinal cell monolayers. The HA proteins of botulinum toxin disrupt intestinal epithelial intercellular junctions to increase toxin absorption. Disruption of the epithelial barrier by botulinum haemagglutinin HA proteins—differences in cell tropism and the mechanism of action between HA proteins of types A or B, and HA proteins of type C.
Clostridial toxins and the central nervous system: Studies on in situ tissues. Botulinum Neurotoxin and Tetanus Toxin. Retrograde transneuronal transport properties of fragment C of tetanus toxin.
Tetanus and botulinum neurotoxins: Turning bad guys into good by research. Mechanism of botulinum neurotoxin B and G entry into hippocampal neurons. SV2 is the protein receptor for botulinum neurotoxin A. The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves. Identification of protein receptor for Clostridium botulinum type B neurotoxin in rat brain synaptosomes.
Botulinum neurotoxins C, E and F bind gangliosides via a conserved binding site prior to stimulation-dependent uptake with botulinum neurotoxin F utilising the three isoforms of SV2 as second receptor. Synaptotagmins I and II act as nerve cell receptors for botulinum neurotoxin G. Lipid rafts act as specialized domains for tetanus toxin binding and internalization into neurons. High sensitivity of mouse neuronal cells to tetanus toxin requires a GPI-anchored protein.
Two carbohydrate binding sites in the H cc -domain of tetanus neurotoxin are required for toxicity. Identification of the protein receptor binding site of botulinum neurotoxins B and G proves the double-receptor concept.
The H cc -domain of botulinum neurotoxins A and B exhibits a singular gangliosside binding site displaying serotype specific carbohydrate interaction. Gangliosides as high affinity receptors for tetanus neurotoxin. Identification of the receptor-binding sites in the carboxyl-terminal half of the heavy chain of botulinum neurotoxin types C and D.
The N-terminal half of the receptor domain of botulinum neurotoxin A binds to microdomains of the plasma membrane. Botulinum neurotoxin A changes conformation upon binding to ganglioside GT1b. Molecular basis for tetanus toxin coreceptor interactions.
The action of botulinum toxin on the neuro-muscular junction. Botulinum toxin inhibits quantal acetylcholine release and energy metabolism in the Torpedo electric organ. Neurotransmitter release is blocked intracellularly by botulinum neurotoxin, and this requires uptake of both toxin polypeptides by a process mediated by the larger chain. Botulinum toxin A blocks glutamate exocytosis from guinea-pig cerebral cortical synaptosomes.
Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E and F compared with the long lasting type A. Measurement of botulinum toxin activity: Towards a new cellular culture assay? Tetanus toxin and botulinum toxins type A and B inhibit glutamate, gamma-aminobutyric acid, aspartate, and met-enkephalin release from synaptosomes.
Clues to the locus of action. Characterization of the inhibitory action of botulinum neurotoxin type A on the release of several transmitters from rat cerebrocortical synaptosomes. Botulinum neurotoxin A blocks synaptic vesicle exocytosis but not endocytosis at the nerve terminal.
Involvement of the constituent chains of botulinum neurotoxins A and B in the blockade of neurotransmitter release. Clostridium neurotoxins influence serotonin uptake and release differently in rat brain synaptosomes.
Botulinum toxin type A blocks the morphological changes induced by chemical stimulation on the presynaptic membrane of Torpedo synaptosomes.
Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Enhanced ATP release from rat bladder urothelium during chronic bladder inflammation: Effect of botulinum toxin A. Exocytotic release of ATP and activation of P2X receptors in dissociated guinea pig stellate neurons. Nicotinamide adenine dinucleotide is released from sympathetic nerve terminals via a botulinum neurotoxin A-mediated mechanism in canine mesenteric artery. Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins.
Inhibition of release of neurotransmitters from rat dorsal root ganglia by a novel conjugate of a Clostridium botulinum toxin A endopeptidase fragment and Erythrina cristagalli lectin. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: Implications for migraine therapy. Head and Face Pain. Botulinum toxin type an inhibits calcitonin gene-related peptide release from isolated rat bladder. Calcitonin gene-related peptide-like immunoreactivity, in botulinum toxin-paralysed rat muscles.
Upregulation of calcitonin gene-related peptide at mouse motor nerve terminals poisoned with botulinum type-A toxin. Possible role in formation and maintenance of neuromuscular junctions. Regulation of motoneuronal calcitonin gene-related peptide CGRP during axonal growth and neuromuscular synaptic plasticity induced by botulinum toxin in rats.
Sweat gland morphology and periglandular innervation in essential palmar hyperhidrosis before and after treatment with intradermal botulinum toxin. Botulinum neurotoxin A attenuates release of norepinephrine but not NPY from vasoconstrictor neurons. Mechanism of action of botulinum toxin on the internal anal sphincter.
Role of the epithelium and acetylcholine in mediating the contraction to 5-hydroxytryptamine in the mouse isolated trachea. Intracellularly injected tetanus toxin inhibits exocytosis in bovine adrenal chromaffin cells.
Introduction of macromolecules into bovine adrenal medullary chromaffin cells and rat pheochromocytoma cells PC12 by permeabilization with streptolysin O: Inhibitory effect of tetanus toxin on catecholamine secretion. The tetanus toxin light chain inhibits exocytosis. Mechanisms of secretion of ATP from cortical astrocytes triggered by uridine triphosphate. SNARE protein-dependent glutamate release from astrocytes. Internalization and proteolytic action of botulinum toxins in CNS neurons and astrocytes.
Glycine in the spinal cord of cats with local tetanus rigidity. Effect of tetanus toxin on the content of glycine, gamma-aminobutyric acid, glutamate, glutamine and aspartate in the rat spinal cord. Differential effects of tetanus toxin on inhibitory and excitatory neurotransmitter release from mammalian spinal cord cells in culture.
Reversible effects of tetanus toxin on striatal-evoked responses and [3H]-gamma-aminobutyric acid release in the rat substantia nigra. In vitro effect of tetanus toxin on GABA release form rat hippocampal slices. Tetanus toxin inhibits the evoked outflow of an inhibitory GABA and an excitatory D-aspartate amino acid from particulate brain cortex.
Endogenous amino acid release from cultured cerebellar neuronal cells: Glutamate transmission is involved in the mechanisms of neuronal degeneration produced by intrahippocampal tetanus toxin in rats. Aspartate release from rat hippocampal synaptosomes.
Regulation of kinetic and pharmacological properties of synaptic NMDA receptors depends on presynaptic exocytosis in rat hippocampal neurones. Release of D, L-threo-beta-hydroxyaspartate as a false transmitter from excitatory amino acid-releasing nerve terminals. Tetanus toxin and botulinum A and C neurotoxins inhibit noradrenaline release from cultured mouse brain. The inhibition by pertussis and tetanus toxins of evoked catecholamine release from intact and permeabilized bovine adrenal chromaffin cells.
Noradrenaline release from permeabilized synaptosomes is inhibited by the light chain of tetanus toxin. Microtubules and microfilaments participate in the inhibition of synaptosomal noradrenaline release by tetanus toxin.
Effect of tetanus toxin on basal and evoked release of 5-hydroxytryptamine and dopamine in rat hippocampus in vivo. Tetanus toxin alters 5-hydroxytryptamine, dopamine, and their metabolites in rat hippocampus measured by in vivo microdialysis. Tetanus toxin inhibits depolarization-induced [3H]serotonin release from rat brain cortex synaptosomes. Inhibition by tetanus toxin of sodium-dependent, high-affinity [3H]5-hydroxytryptamine uptake in rat synaptosomes. Serotonin transport is modulated differently by tetanus toxin and growth factors.
Tetanus toxin modulates serotonin transport in rat-brain neuronal cultures. Serotonin transporter phosphorylation modulated by tetanus toxin. A role for cGMP during tetanus toxin blockade of acetylcholine release in the rat pheochromocytoma PC12 cell line. Studies on the intoxication pathway of tetanus toxin in the rat pheochromocytoma PC12 cell line.
Binding, internalization, and inhibition of acetylcholine release. Tetanus toxin blocks potassium-induced transmitter release and rearrangement of intramembrane particles at pure cholinergic synaptosomes.
Suppression of 3H-acetylcholine release from primary nerve cell cultures by tetanus and botulinum-A toxin. Light chain of tetanus toxin intracellularly inhibits acetylcholine release at neuro-neuronal synapses, and its internalization is mediated by heavy chain. Astrocytic glutamate release-induced transient depolarization and epileptiform discharges in hippocampal CA1 pyramidal neurons.
Tetanus toxin-mediated cleavage of cellubrevin impairs exocytosis of transferrin receptor-containing vesicles in CHO cells. The journey of tetanus and botulinum neurotoxins in neurons. Analysis of retrograde transport in motor neurons reveals common endocytic carriers for tetanus toxin and neutrophin receptor p75 NTR. Uptake and transport of clostridium neurotoxins. Tetanus toxin is transported in a novel neuronal compartment characterized by a specialized pH regulation.
Tetanus toxin is internalized by a sequential clathrin-dependent mechanism initiated within lipid microdomains and independent of epsin1. Rab5 and Rab7 control endocytic sorting along the axonal retrograde transport pathway.
Recombinant forms of tetanus toxin engineered for examining and exploiting neuronal trafficking pathways. Retrograde trans-synaptic transfer of green fluorescent protein allows the genetic mapping of neuronal circuits in transgenic mice. Membrane Interaction of botulinum neurotoxin A translocation T domain. The belt region is a regulatory loop for membrane interaction.
Translocation of botulinum neurotoxin light chain protease through the heavy chain channel. Crucial role of the disulfide bridge between botulinum neurotoxin light and heavy chains in protease translocation across membranes. Translocation of botulinum neurotoxin light chain protease by the heavy chain protein-conducting channel.
A conserved motif in transmembrane helix 1 of diphtheria toxin mediates catalytic domain delivery to the cytosol. The role of the synaptic protein snap in the potency of botulinum neurotoxin type A. A molecular basis underlying differences in the toxicity of botulinum serotypes A and E. Botulinum neurotoxin C1 cleaves both syntaxin and SNAP in intact and permeabilized chro-maffin cells: Correlation with its blockade of catecholamine release.
Domains and amino acid residues controlling the formation of enzyme-substrate complexes and cleavage. Disruption of syntaxin-mediated protein interactions blocks neurotransmitter secretion. Clostridial neurotoxins and substrate proteolysis in intact neurons: Botulinum neurotoxin C acts on synaptosomal-associated protein of 25 kDa.
Attack of the nervous system by clostridial toxins: Physical findings, cellular and molecular actions. The Sourcebook of Bacterial Protein Toxins. Persistence of botulinum neurotoxin action in cultured spinal cord cells. Rescue of exocytosis in botulinum toxin A-poisoned chromaffin cells by expression of cleavage-resistant SNAP Plasma membrane localization signals in the light chain of botulinum neurotoxin. Synaptic vesicle membrane fusion complex: Syntaxin modulation of slow inactivation of N-type calcium channels.
Syntaxin I modulation of presynaptic calcium channel inactivation revealed by botulinum toxin C1. Syntaxin modulation of calcium channels in cortical synaptosomes as revealed by botulinum toxin C1. Calcium-dependent acetylcholine release from Xenopus oocytes: Simultaneous ionic currents and acetylcholine release recordings.
Cleavage of syntaxin prevents G-protein regulation of presynaptic calcium channels. The kDa synaptosome-associated protein SNAP binds and inhibits delayed rectifier potassium channels in secretory cells. A model for receptor-regulated calcium entry. The molecular choreography of a store-operated calcium channel. Evidence for a vesicle-mediated maintenance of store-operated calcium channels in a human embryonic kidney cell line.
Vesicle fusion or reversible trafficking and de novo conformational coupling? Functional impact on channel gating. Modal regulation of channel activation and inactivation gating. A single mutation in the recombinant light chain of tetanus toxin abolishes its proteolytic activity and removes the toxicity seen after reconstitution with native heavy chain. New tools for dissecting exocytosis. Botulinum A like type B and tetanus toxins fulfils criteria for being a zinc-dependent protease. Cenci Di Bello I.
Antagonism of the intracellular action of botulinum neurotoxin type A with monoclonal antibodies that map to light-chain epitopes. Covalent modification of synapsin I by a tetanus toxin-activated transglutaminase. Tetanus toxin potently stimulates tissue transglutaminase. A possible mechanism of neurotoxicity. The role of transglutaminase in the mechanism of action of tetanus toxin.
Role of transglutaminase in [3H]5-HT release from synaptosomes and in the inhibitory effect of tetanus toxin. An enigmatic enzyme with diverse functions. Crosslinking enzymes with pleiotropic functions. Tissue-transglutaminase in rat and human brain: Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release. Vitamin A stimulation of insulin secretion: A role for transglutaminase in neurotransmitter release by rat brain synaptosomes.
Synapsin controls both reserve and releasable synaptic vesicle pools during neuronal activity and short-term plasticity in Aplysia. Lack of synapsin I reduces the readily releasable pool of synaptic vesicles at central inhibitory synapses. Tetanus toxin inhibits depolarization-stimulated protein phosphorylation in rat cortical synaptosomes: Effect on synapsin I phosphorylation and translocation. Exploring the functional domain and the target of the tetanus toxin light chain in neurophysial terminals.
Protease activity of botulinum neurotoxin type E and its light chain: Tetanus and botulinum A toxins inhibit stimulated F-actin rearrangement in chromaffin cells. Tetanus toxin light chain expression in Sertoli cells of transgenic mice causes alterations of the actin cytoskeleton and disrupts spermatogenesis.
Botulinum toxin type A targets RhoB to inhibit lysophosphatidic acid-stimulated actin reorganization and acetylcholine release in nerve growth factor-treated PC12 cells. In vivo translocation and down-regulation of protein kinase C following intraventricular administration of tetanus toxin. Tetanus toxin enhances protein kinase C activity translocation and increases polyphosphoinositide hydrolysis in rat cerebral cortex preparations.
The C-terminal domain of the heavy chain of tetanus toxin rescues cerebellar granule neurones from apoptotic death: Involvement of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Structure and mode of action of clostridial glucosylating toxins: Glucosylation of Rho proteins by Clostridium difficile toxin B.
Nature London ; The enterotoxin from Clostridium difficile ToxA monoglucosylates the Rho proteins. Ras, Rap, and rac small GTP-binding proteins are targets for Clostridium sordellii lethal toxin glucosylation. Functional consequences of monoglucosylation of Ha-Ras at effector domain amino acid threonine Structural consequences of monoglucosylation of Ha-Ras by Clostridium sordellii lethal toxin.
Clostridial Rho-inhibiting protein toxins. C3 exoenzymes, novel insights into structure and action of Rho-ADP-ribosylating toxins. Involvement of Rho GTPases in calcium-regulated exocytosis from adrenal chromaffin cells. Evidence for differential roles of the Rho subfamily of GTP-binding proteins in glucose- and calcium-induced insulin secretion from pancreatic beta cells. Inhibition of Fc epsilon-RI-mediated activation of rat basophilic leukemia cells by Clostridium difficile toxin B monoglucosyltransferase J.
Degeneration and regeneration of murine skeletal neuromuscular junctions after intramuscular injection with a sublethal dose of Clostridium sordellii lethal toxin. Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability.
Nerves and intestinal mast cells modulate responses to enterotoxins. Exocyst III--makes a family. Ben El Hadj N.
G-protein-stimulated phospholipase D activity is inhibited by lethal toxin from Clostridium sordellii in HL cells. Interaction of the membrane-inserted diphtheria toxin T domain with peptides and its possible implications for chaperone-like T domain behavior. Evidence for a role of the small GTPase Rac1. A role for monomeric G-proteins in synaptic plasticity in the rat dentate gyrus in votro.
Synaptic structure and diffusion dynamics of synaptic receptors. A double-edged sword during the host-pathogen interaction. The molecular mechanism of pneumolysin, a virulence factor from Streptococcus pneumoniae. Structural elements of the cholesterol-dependent cytolysins that are responsible for their cholesterol-sensitive membrane interactions. Structure, function, and role in disease.
Specific protein-membrane contacts are required for prepore and pore assembly by a cholesterol-dependent cytolysin. The mechanism of pore assembly for a cholesterol-dependent cytolysin: Prepore to pore transition of a cholesterol-dependent cytolysin visualized by electron microscopy.
Conformational changes that effect oligomerization and initiate pore formation are triggered throughout perfringolysin O upon binding to cholesterol. Structures of perfringolysin O suggest a pathway for activation of cholesterol-dependent cytolysins.
Structural insights into the membrane-anchoring mechanism of a cholesterol-dependent cytolysin. Mechanism of membrane insertion of a multimeric beta-barrel protein: Perfringolysin O creates a pore using ordered and coupled conformational changes. The mechanism of membrane insertion of a cholesterol-dependent cytolysin: A novel paradigm for pore-forming toxins. Structure of a cholesterol-binding thiol-activated cytolysin and a model of its membrane form.
Vertical collapse of a cytolysin prepore moves its transmembrane beta-hairpins to the membrane. The role of pneumolysin in pneumococcal pneumonia and meningitis. Pneumococcal pneumolysin and H 2 O 2 mediate brain cell apoptosis during meningitis. Pneumolysin causes neuronal cell death through mitochondrial damage. Neurotoxicity of pneumolysin, a major pneumococcal virulence factor, involves calcium influx and depends on activation of p38 mitogen-activated protein kinase. Clostridium perfringens epsilon toxin increases the small intestinal permeability in mice and rats.
Clostridium perfringens epsilon toxin is absorbed from different intestinal segments of mice. Pathogenesis of brain damage produced in sheep by Clostridium perfringens type D epsilon toxin: The Clostridium perfringens epsilon-toxin. Distribution of labeled Clostridium perfringens epsilon toxin in mice. High-affinity binding of Clostridium perfringens epsilon-toxin to rat brain. Clostridium perfringens prototoxin-induced alteration of endothelial barrier antigen EBA immunoreactivity at the blood brain barrier BBB Exp.
The use of an imunoperoxidase technique to investigate by light and electron microscopy the sites of binding of Clostridium welchii type D e-toxin in mice. Neuronal damage produced in rat brains by Clostridium perfringens type D epsilon-toxin. Neurotoxicity of Clostridium perfringens epsilon-toxin for the rat hipocampus via glutamanergic system. Clostridium perfringens epsilon toxin causes excessive release of glutamate in the mouse hippocampus. Structural studies on epsilon toxin from Clostridium perfringens.
Protein Toxins of the Genus Clostridium and Vaccination. Clostridium perfringens epsilon-toxin acts on MDCK cells by forming a large membrane complex. Clostridium perfringens epsilon-toxin induces a rapid change in cell membrane permeability to ions and forms channels in artificial lipid bilayers. Lethal toxin from Clostridium sordellii induces apoptotic cell death by disruption of mitochondrial homeostasis in HL cells. Pore-forming epsilon toxin causes membrane permeabilization and rapid ATP depletion-mediated cell death in renal collecting duct cells.
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One of these is the heterodimeric neurotoxin b -bungarotoxin, which acts by inhibiting the release of acetylcholine from motor nerve endings, one of the most investigated steps in neuromuscular transmission 1,16,18,. Six isoforms of b -bungarotoxin b 1 - b 6 from the venom of Bungarus multicinctus 17 and five isoforms of b -bungarotoxin b 1 - b 5 caeruleotoxin from the venom of B.
It acts presynaptically by binding via the protein-inhibitor-like subunit to a presynaptic potassium channel and then blocking neurotransmission with the second subunit, which has phospholipase A 2 activity, thus altering acetylcholine release in both the peripheral and central nervous systems. Although the presynaptic action of b -bungarotoxin has been established, there is also evidence for its postsynaptic action 26 in mammalian skeletal muscle. Following exposure of nerve muscle preparation to toxin, the frequency of miniature end plate potentials MEPP generally undergoes a triphasic change.
The three phases are: Usually the muscle membrane potential and the directly elicited muscle action potential remain unchanged On frog sartorius preparation 1, 3, 20 , it has been reported that b -bungarotoxin causes a marked decrease in MEPP frequency in a matter of minutes after being added to the bath, and that it may last about 10 min. It has been suggested 5 that phase one is caused by the binding of b -bungarotoxin to the presynaptic membrane, but the reason why this binding results in changes in the MEPP frequency has not been explained.
Aimed at discovering and developing drugs, we initiated our efforts to isolate, purify and characterize Bungarus caeruleus toxin to treat painful neurological movement disorders, also known as dystonias, in lieu of botulinum toxin, which is highly antigenic, expensive, and nerve damaging in nature. Though this suggestion is largely hypothetical in nature, it is sound when biochemical characteristics of both toxins are compared.
Causing selective muscle paralysis is the main concern to alleviate human suffering. Development of this concept is mainly a result of intuitive empirical work by the clinicians with collaborative scientific studies generated secondarily. While some toxins have lead directly to their use as therapeutic agents, others have provided insight into selective pharmacological actions.
Although many toxins are too large or too poorly absorbed to be used as drugs, advances in techniques for analyzing three-dimensional structure and computer-aided drug design should make it likely that toxins will act as model compounds in drug discovery. We wish to thank all our colleagues from Department of Biochemistry, Dharwad, and elsewhere, without whom it would not have been possible to carry out this work. We are especially grateful to Shri Shastri, principal of Sonia College of Pharmacy, for providing us all the facility required for this work.
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Butantan , , 33,
Clostridial Neurotoxins and Substrate Proteolysis in Intact Neurons
Botulinum neurotoxin is one of three substances produced by Clostridium botulinum that The other two are the botulinum binary toxin, which acts somewhat. H. Bigalke, H. Müller and F. Dreyer. Botulinum A neurotoxin unlike tetanus toxin acts via a neuraminidase sensitive structure. Toxicon24, – , The neurotoxin purified from the venom of Bungarus caeruleus causes a . One of these is the heterodimeric neurotoxin b-bungarotoxin, which acts by inhibiting .