Tetanus and Botulinum Neurotoxins

Wellhöner, H. H.

doi:10.1007/978-3-642-85117-9_11

Cited by 17 publications

(15 citation statements)

References 358 publications

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“…TeNT may also bind to sympathetic adrenergic ¢bres (reviewed by Wellhoner (1992), and by Habermann & Dreyer (1986)). In vitro, CNTs are capable of binding to a variety of non-neuronal cells, however only at concentrations far exceeding those of clinical signi¢cance.…”

Section: Neurospecific Bindingmentioning

confidence: 99%

“…Electrophysiological studies clearly showed that BoNTs block neuroexocytosis at peripheral terminals, whereas TeNTcauses the same e¡ect at CNS synapses of the spinal cord (Wellhoner 1992). These di¡erent ¢nal destinations must be determined by speci¢c receptors of TeNT and BoNTs which drive them to di¡erent intracellular routes.…”

Section: Neurospecific Bindingmentioning

confidence: 99%

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Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses

Pellizzari

Rossetto

Schiavo

et al. 1999

Phil. Trans. R. Soc. Lond. B

261

197

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The clostridial neurotoxins responsible for tetanus and botulism are proteins consisting of three domains endowed with di¡erent functions: neurospeci¢c binding, membrane translocation and proteolysis for speci¢c components of the neuroexocytosis apparatus. Tetanus neurotoxin (TeNT) binds to the presynaptic membrane of the neuromuscular junction, is internalized and transported retroaxonally to the spinal cord. The spastic paralysis induced by the toxin is due to the blockade of neurotransmitter release from spinal inhibitory interneurons. In contrast, the seven serotypes of botulinum neurotoxins (BoNTs) act at the periphery by inducing a £accid paralysis due to the inhibition of acetylcholine release at the neuromuscular junction. TeNT and BoNT serotypes B, D, F and G cleave speci¢cally at single but di¡erent peptide bonds, of the vesicle associated membrane protein (VAMP) synaptobrevin, a membrane protein of small synaptic vesicles (SSVs). BoNT types A, C and E cleave SNAP-25 at di¡erent sites located within the carboxyl-terminus, while BoNT type C additionally cleaves syntaxin. The remarkable speci¢city of BoNTs is exploited in the treatment of human diseases characterized by a hyperfunction of cholinergic terminals.

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Section: Neurospecific Bindingmentioning

confidence: 99%

Section: Neurospecific Bindingmentioning

confidence: 99%

Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses

Pellizzari

Rossetto

Schiavo

et al. 1999

Phil. Trans. R. Soc. Lond. B

261

197

View full text Add to dashboard Cite

show abstract

“…The toxigenic light chain (50 kDa) remains linked by a single disulfide bond to the binding domain of the targeting heavy chain (100 kDa). The principal targets of TeTx are both the central and peripheral nervous systems where inhibition of neurotransmitter release has been demonstrated (for review, see Mellanby, 1984;van Heyningen, 1986;Wellhöner, 1992;Niemann et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Tetanus Toxin Enhances Protein Kinase C Activity Translocation and Increases Polyphosphoinositide Hydrolysis in Rat Cerebral Cortex Preparations

Gil

Ruiz‐Meana

Álava

et al. 1998

Journal of Neurochemistry

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Abstract:Tetanus toxin (TeTx) has been recently demonstrated to be a Zn 2~-dependentendopeptidase that cleaves synaptobrevin, a protein in part responsible for neurotransmitter release. Nevertheless, certain aspects of TeTx action, for example, the causal relationship between TeTx and protein kinase C (PKC; EC 2.7.1.37) activity cannot be explained by this cleavage alone. In the present study, primary neurons from fetal rat brain, synaptosomes, and whole slices have been used to examine this issue. Low doses of TeTx ( 10_8 M) caused PKC activity translocation in a manner similar to that produced by 1 2-O-tetradecanoylphorbol 13-acetate (TPA). TPA ( 10M) caused sustained PKC activity translocation, whereas TeTx produced translocation followed by relocation, depending on the dose and time of exposure. Immunoidentification with a monoclonal antibody recognizing both a and /3 isoforms revealed that TeTx induced moderate losses of PKC in the cytosolic fraction, without a comparable increase in the particulate fraction. Although moderate losses of activity were also noticed in the cytosolic fraction, the inconsistency with respect to activity translocation may be explained by translocation of additional PKC isoforms that are not identified by the antibody. Comparable levels of water-soluble inositol phosphate-labeled intermediates were obtained after treatment of cerebral cells and/or cortical brain slices with TeTx. Significant increases of 19 and 114% in the watersoluble myo-[2-3H]inositol-labeled inositol phosphate metabolites were found in cerebral cell culture and brain slices, respectively, after treatment with 10~8M TeTx. TeTx (10_8 M) increased to the same degree the watersoluble inositol phosphate levels as did serotonin (10-M ) or carbachol (10-6 M). lt is suggested that part of the signaling cascade of TeTx consists of a component involving inositol phospholipid hydrolysis, which is associated with PKC activity translocation. Key Words: Tetanus toxin-Protein kinase C-Phorbol ester-Neuronal cultures-Polyphosphoinositide hydrolysis-Phospholipase C-Synaptosomes.

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“…TeNT enters the nervous system at the neuromuscular synapse as well, but then it migrates retrogradely inside the motor axon and is discharged in the spinal cord where it affects inhibitory interneurons. The subsequent block of release of inhibitory neurotransmitters leads to a failure to counterbalance excitatory stimuli, resulting in the spastic paralysis of all striated muscles that is characteristic of tetanus (Mellanby and Green, 1981; Wellhoner, 1992; Montecucco and Schiavo, 1993). BoNT and TeNT therefore exert their action by blocking neurotransmitter release at peripheral and central synapses, respectively.…”

mentioning

confidence: 99%

Internalization and Proteolytic Action of Botulinum Toxins in CNS Neurons and Astrocytes

Verderio

Coco

Rossetto

et al. 1999

Journal of Neurochemistry

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Tetanus and botulinum toxins bind and are internalized at the neuromuscular junction. Botulinum neurotoxins (BoNTs) enter the cytosol at the motor nerve terminal; tetanus neurotoxin (TeNT) proceeds retroaxonally inside the motor axon to reach the spinal cord inhibitory interneurons. Although the major target of BoNTs is the peripheral cholinergic terminals, CNS neurons are susceptible to intoxication as well. We investigated the route of entry and the proteolytic activity of BoNT/B and BoNT/F in cultured hippocampal neurons and astrocytes. We show that, differently from TeNT, which enters hippocampal neurons via the process of synaptic vesicle (SV) recycling, BoNTs are internalized and cleave the substrate synaptobrevin/VAMP2 via a process independent of synaptic activity. Labeling of living neurons with Texas Red-conjugated BoNTs and fluoresceinated dextran revealed that these toxins enter hippocampal neurons via endocytic processes not mediated by SV recycling. Botulinum toxins also exploit endocytosis to enter cultured astrocytes, where they partially cleave cellubrevin, a ubiquitous synaptobrevin/VAMP isoform. These results indicate that, in spite of their closely related protein structure, TeNT and BoNTs use different routes to penetrate hippocampal neurons. These findings bear important implications for the identification of the protein receptors of clostridial toxins.

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Tetanus and Botulinum Neurotoxins

Cited by 17 publications

References 358 publications

Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses

Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses

Tetanus Toxin Enhances Protein Kinase C Activity Translocation and Increases Polyphosphoinositide Hydrolysis in Rat Cerebral Cortex Preparations

Internalization and Proteolytic Action of Botulinum Toxins in CNS Neurons and Astrocytes

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