Tetanus neurotoxin release

The SNAREs involved in the fusion of synaptic vesicles and of secretory granules in neuroendocrine cells, referred to as neuronal SNAREs, have been intensely studied and serve as a paradigm for all SNAREs. They include syntaxin 1A and SNAP-25 at the presynaptic membrane and synaptobrevin 2 (also referred to as VAMP 2) at the vesicle membrane. Their importance for synaptic neurotransmission is documented by the fact that the block in neurotransmitter release caused by botulinum and tetanus neurotoxins is due to proteolysis of the neuronal SNAREs (Schiavo et al. 2000). Genetic deletion of these SNAREs confirmed their essential role in the last steps of neurotransmitter release. Intriguingly, analysis of chromaffin cells from KO mice lacking synaptobrevin or SNAP-25 showed that these proteins can be at least partially substituted by SNAP-23 and cellubrevin, respectively (Sorensen et al. 2003 Borisovska et al. 2005), i.e., the corresponding SNAREs involved in constitutive exocytosis. 

Hughes R, Whaler BC (1962) Influence of nerve-ending activity and of drugs on the rate of paralysis of rat diaphragm preparations by cl. botulinum type a toxin. J Physiol 160 221-33 Humeau Y, Doussau F, Grant NJ, Poulain B (2000) How botulinum and tetanus neurotoxins block neurotransmitter release. Biochimie 82 427 16... 

Tetanus is a syndrome that is often lethal, characterized by a spastic paralysis. Death follows bodily exhaustion and occurs by respiratory failure or circulatory collapse. For twenty four centuries tetanus had been considered a neurologic disease until the identification of Clostridium tefani, the bacterium that causes tetanus by the release of a protein toxin, named tetanus neurotoxin (TeTx)(Faber, 1890 Kitasato, ... 

Ashton, A. C., de Paiva, A. M., Poulain, B., Tauc, L. and Dolly, J. 0., 1993, Factors underlying the characteristic inhibition of the neuronal release of transmitters by tetanus and various botulinum neurotoxins. In Botulinum and Tetanus Neurotoxins Neurotransmission and Biomedical Aspects (B. R. DasGupta, ed.), Plenum Press, New York. pp. 191-213. 

Botulinum neurotoxins (A-G), tetanus toxin Synaptic peptides a) Synapto-brevin b) Syntaxin c) SNAP25 Zinc dependent endoprotease Cleavage of synaptic peptides Inhibition of transmitter release (tetanus, botulism)... 

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. 

Altered release. Tetanus is an infectious disease caused by the bacterium Clostridium tetani. This bacterium produces a neurotoxin active on inhibitory synapses in the spinal cord. Motor neurons, which supply skeletal muscle and cause contraction, have cell bodies that lie in the spinal cord. Under normal circumstances, these motor neurons receive excitatory and inhibitory inputs from various sources. The balance of these inputs results in the appropriate degree of muscle tone or muscle contraction. Tetanus toxin prevents the release of gamma amino butyric acid (GABA), an important neurotransmitter active at these inhibitory synapses. Eliminating inhibitory inputs results in unchecked or unmodulated excitatory input to the motor neurons. The resulting uncontrolled muscle spasms initially occur in the muscles of the jaw, giving rise to the expression lockjaw. The muscle spasms eventually... 

G. Schiavo, F. Benfenati, B. Poulain, O. Rossetto, P. Polverino de Laureto, B. R. Das-Gupta, C. Montecucco, Tetanus and Botulinum-B Neurotoxins Block Neurotransmitter Release by Proteolytic Cleavage of Synaptobrevin , Nature 1992a, 359, 832-835 G. Schiavo, O. Rossetto, A. Santucci, B. R. DasGupta, C. Montecucco, Botulinum Neurotoxins are Zinc Proteins , J. Biol. Chem. 1992b, 267, 23479-23483. 

Poulain, B., Mochida, S., Weller, U., Hogy, B., Habermann, E., Wadsworth, J. D., Shone, C.C., Dolly, J.O. and Tauc, L., Heterologous combinations of heavy and light chains from botulinum neurotoxin A and tetanus toxin inhibit neurotransmitter release in Aplysia, J. Biol. Chem., 266, 9580-9585, 1991. 

Tetanus is a condition characterised by prolonged, involuntary contraction of the skeletal muscles. The condition can be localised or generalised. Tetanus is caused by the bacterium Clostridium tetani, an obligate, anaerobic, Gram-positive rod-shaped bacterium. The pathogen produces an exotoxin called tetanospasmin. Tetanospasmin is a potent neurotoxin which blocks neurotransmitter release from inhibitory neurons resulting in muscular contractions. C. tetani is not an invasive microbe, rather the spread of the toxin is due to... 

Neurotoxins, such as the clostridial neurotoxins responsible for tetanus and botulism. These are metallo-proteases that enter nerve cells and block neurotransmitter release via zinc-dependent cleavage of protein components of the neuroexocytosis apparatus. 

Tetanus is characterised by a prolonged contraction of skeletal muscle fibres the neurotoxin responsible is from Clostridium tetani. The toxin initially binds to peripheral nerve terminals and is then transported within the axon and across synaptic junctions until it reaches the central nervous system (CNS). Here it attaches to ganghosides at the presynaptic inhibitory motor nerve endings and is taken up into the axon by endocytosis. The effect of the toxin is to block the release of inhibitory neurotransmitters (glycine and gamma-amino butyric acid), which are required to check the nervous impulse, leading to the generalised muscular spasms characteristic of tetanus. 

Matsuda M, Lei DL, Sugimoto N, Ozutsumi K, OkabeT (1989) Isolation, purification and characterization of fragment B, the NH2-terminal half of the heavy chain of tetanus toxin. In Infect. Immun. 57 3588-93 Matthews BW (1988) Structural basis of the action of thermolysin and related zinc peptidases.In Acc. Chem. Res. 21 333-40 Mclnnes C, Dolly JO (1990) Ca -dependent noradrenaline release from perme-abilised PC 12 cells is blocked by botulinum neurotoxin A or its light chain. In FEBS Lett. 261 323-6... 

Schiavo G, Bentenati F, Poulain B, Rossetto O, Polverino de Laureto P, DasGupta BR, Montecucco C (1992 a) Tetanus and botulinum-B neurotoxins block neurotransmitter release by a proteolytic cleavage of synaptobrevin, In Nature 359 832-5... 

Schiavo G, Poulain B, Rossetto O, Benfenati F, Tauc L, Montecucco C (1992 b) Tetanus toxin is a zinc protein and its inhibition of neurotrasmitter release and protease activity depend on zinc. In EMBOJ. 11 3577-83 Schiavo G, Rossetto O, Santucci A, DasGupta BR, Montecucco C (1992 c) Botulinum neurotoxins are zinc proteins. In J. Biol. Chem. 267 23479-83 Schiavo G, Rossetto O, Catsicas S, Polverino de Laureto P, DasGupta BR, Benfenati F, Montecucco C (1993 a) Identification of the nerve-terminal targets of botulinum neurotoxins serotypes A, D and E. In J. Biol. Chem. 268 23784-7 Schiavo G, Santucci A, DasGupta BR, Metha PP, Jontes J, Benfenati F, Wilson MC, Montecucco C (1993 b) Botulinum neurotoxins serotypes A and E cleave SNAP-25 at distinct COOH-terminal peptide bonds. In FEBS Lett. 335 99-103 Schiavo G, Shone CC, Rossetto O, Alexandre FCG, Montecucco C (1993 c) Botulinum neurotoxin serotype F is a zinc endopeptidase specific for VAMP/synOp-tobrevin. In J. Biol. Chem. 268 11516-9... 

Tetanus toxin poisoning produces tetanus, i.e. muscle contractions resulting in spastic paralysis. In contrast, Botulinum neurotoxins cause botulism, which is characterized by flaccid paralysis. This difference reflects differences in the anatomical level of action of these toxins. TeTx acts primarily on the CNS where it blocks exocytosis from inhibitory glycinergic synapses in the spinal cord. Loss of inhibitory control results in motoneuron firing. BoNTs act primarily in the periphery where they inhibit acetylcholine release at the neuromuscular junctions. 

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