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This content will go in the SNARE (protein) page, under the Toxins heading I will add a Tetanus Neurotoxin (TeNT) subheading.

Tetanus Neurotoxin (TeNT)[edit]

The breakdown of responsibilities and mechanisms of the heavy (HC) and light chain (LC) of tetanus neurotoxin: The HC assists in binding of TeNT to both the ganglioside receptor and the final receptor. Once TeNT is in the vesicle in the inhibitory interneuron space the HC assists in translocation of the LC into the cytoplasm. Then the LC, characterized by zinc endopeptidase activity, inhibits neurotransmission by cleavage of synaptobrevin 1.

Tetanus toxin, or TeNT, is composed of a heavy chain (100KDa) and a light chain (50kDa) connected by a disulfide bond. The heavy chain is responsible for neurospecific binding of TeNT to the nerve terminal membrane, endocytosis of the toxin, and translocation of the light chain into the cytosol. The light chain has zinc-dependent endopepdtidase or more specifically matrix metalloproteinase (MMP) activity through which cleaveage of synaptobrevin or VAMP is carried out.[1]

For the light chain of TeNT to be activated one atom of zinc must be bound to every molecule of toxin.[2] When zinc is bound reduction of the disulfide bond will be carried out primarily via the NADPH-thioredoxin reductase-thioredoxin redox system.[3] Then the light chain is free to cleave the Gln76-Phe77 bond of synaptobrevin.[1] Cleavage of synaptobrevin affects the stability of the SNARE core by restricting it from entering the low energy conformation which is the target for NSF binding.[4] This cleavage of synaptobrevin is the final target of TeNT and even in low doses the neurotoxin will inhibit neurotransmitter exocytosis.

References[edit]

  1. ^ a b Schiavo, G; Benfenati, F; Poulain, B; Rossetto, O; Polverino de Laureto, P; DasGupta, BR; Montecucco, C (29 October 1992). "Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin". Nature. 359 (6398): 832–5. PMID 1331807.
  2. ^ Schiavo, G; Poulain, B; Rossetto, O; Benfenati, F; Tauc, L; Montecucco, C (October 1992). "Tetanus toxin is a zinc protein and its inhibition of neurotransmitter release and protease activity depend on zinc". The EMBO journal. 11 (10): 3577–83. PMID 1396558.
  3. ^ Pirazzini, M; Bordin, F; Rossetto, O; Shone, CC; Binz, T; Montecucco, C (16 January 2013). "The thioredoxin reductase-thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals". FEBS letters. 587 (2): 150–5. PMID 23178719.
  4. ^ Pellegrini, LL; O'Connor, V; Lottspeich, F; Betz, H (2 October 1995). "Clostridial neurotoxins compromise the stability of a low energy SNARE complex mediating NSF activation of synaptic vesicle fusion". The EMBO journal. 14 (19): 4705–13. PMID 7588600.

External Links[edit]



This is what is currently in the Mechanisms section on the Tetanospasmin page:

Mechanism[edit]

Tetanus toxin causes violent spastic paralysis by blocking the release of γ-aminobutyric acid (GABA). GABA is a neurotransmitter that inhibits motor neurons.[1]

The action of the A-chain stops the affected neurons from releasing the inhibitory neurotransmitters GABA and glycine, but also excitatory transmitters,[2] by degrading the protein synaptobrevin 2.[3] The consequence of this is dangerous overactivity in the muscles from the smallest stimulus—the failure of inhibition of motor reflexes by sensory stimulation. This causes generalized contractions of the agonist and antagonist musculature, termed a tetanic spasm.

References[edit]

  1. ^ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009-05-28). Robbins and Cotran Pathologic Basis of Disease, Professional Edition: Expert Consult - Online (Robbins Pathology) (Kindle Locations 19359-19360). Elsevier Health. Kindle Edition.
  2. ^ Kanda K; Takano K (February 1983). "Effect of tetanus toxin on the excitatory and the inhibitory post-synaptic potentials in the cat motoneurone". J Physiol. 335: 319–333. PMC 1197355. PMID 6308220.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Schiavo G; Benfenati F; Poulain B; Rossetto O; Polverino de Laureto P; DasGupta BR; Montecucco C (October 29, 1992). "Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin". Nature. 359 (6398): 832–5. doi:10.1038/359832a0. PMID 1331807.{{cite journal}}: CS1 maint: multiple names: authors list (link)

I'm going to add this image to the Tetanospasmin page.

Tetanus Toxin Light Chain C Fragment

This is what the Mechanism section will look like after I edit it: Also, just as a heads up, you don't have to worry about checking the last 3 references, they were ones that were already on the page.

Mechanism[edit]

The mechanism of TeNT action can be broken down and discussed in 6 different steps.

Transport
  1. Specific binding in the periphery neurons
  2. Retrograde axonal transport to the central nervous system (CNS) inhibitory interneurons
  3. Transcytosis from the axon into the inhibitory interneurons
Action
  1. Temperature and pH mediated translocation of the light chain into the cytosol
  2. Reduction of the disulphide bond between the light and heavy chain
  3. Cleavage of synaptobrevin

The first three steps outline the travel of tetanus from the peripheral nervous system to where it is taken up to the CNS and has its final effect. The last three steps document the changes necessary for the final mechanism of the neurotoxin.

Transport to the CNS inhibitory interneurons begins with The B-chain mediating the neurospecific binding of TeNT to the nerve terminal membrane. It binds to GT1b polysialogangliosides, similarly to the botulinum neurotoxin. It also binds another poorly characterized GPI anchored protein receptor more specific to TeNT.[1] [2] Both the ganglioside and the GPI anchored protein are located in lipid microdomains and both are requisite for specific TeNT binding.[2] Once it is bound the neurotoxin is then endocytosed into the nerve and begins to travel through the axon to the spinal neurons. The next step, transcytosis from the axon into the CNS inhibitory interneuron, is one of the least understood parts of TeNT action. At least two pathways are involved, one that relies on the recycling of synaptic vesicle 2 (SV2) system and one that does not.[3]

Once the vesicle is in the inhibitory interneuron its translocation is mediated by pH and temperature, specifically a low or acidic pH in the vesicle and standard physiological temperatures.[4] [5] Once the toxin has been translocated into the cytosol the disulfide bond is reduced, mainly by the NADPH-thioredoxin reductase-thioredoxin redox system and the light chain is free to cleave the Gln76-Phe77 bond of synaptobrevin.[6] Cleavage of synaptobrevin affects the stability of the SNARE core by restricting it from entering the low energy conformation which is the target for NSF binding.[7] Synaptobrevin is an integral V-SNARE necessary for vesicle fusion to membranes. The cleavage of synaptobrevin is the final target of TeNT and even in low doses the neurotoxin will inhibit neurotransmitter exocytosis in the inhibitory interneurons. The blockage of these neurotransmitters is what causes the physiological effects that accompany TeNT, specifically the blockage of the neurotransmitters GABA and glycine.

Tetanus toxin causes violent spastic paralysis by blocking the release of γ-aminobutyric acid (GABA). GABA is a neurotransmitter that inhibits motor neurons.[8]

The action of the A-chain stops the affected neurons from releasing the inhibitory neurotransmitters GABA and glycine, but also excitatory transmitters,[9] by degrading the protein synaptobrevin 2.[10] The consequence of this is dangerous overactivity in the muscles from the smallest stimulus—the failure of inhibition of motor reflexes by sensory stimulation. This causes generalized contractions of the agonist and antagonist musculature, termed a tetanic spasm.

References[edit]

  1. ^ Munro, P; Kojima, H; Dupont, JL; Bossu, JL; Poulain, B; Boquet, P (30 November 2001). "High sensitivity of mouse neuronal cells to tetanus toxin requires a GPI-anchored protein". Biochemical and biophysical research communications. 289 (2): 623–9. PMID 11716521.
  2. ^ a b Winter, A; Ulrich, WP; Wetterich, F; Weller, U; Galla, HJ (17 June 1996). "Gangliosides in phospholipid bilayer membranes: interaction with tetanus toxin". Chemistry and physics of lipids. 81 (1): 21–34. PMID 9450318.
  3. ^ Yeh, FL; Dong, M; Yao, J; Tepp, WH; Lin, G; Johnson, EA; Chapman, ER (24 November 2010). "SV2 mediates entry of tetanus neurotoxin into central neurons" (PDF). PLoS pathogens. 6 (11): e1001207. PMID 21124874.
  4. ^ Pirazzini, M; Rossetto, O; Bertasio, C; Bordin, F; Shone, CC; Binz, T; Montecucco, C (4 January 2013). "Time course and temperature dependence of the membrane translocation of tetanus and botulinum neurotoxins C and D in neurons". Biochemical and biophysical research communications. 430 (1): 38–42. PMID 23200837.
  5. ^ Burns, JR; Baldwin, MR (8 August 2014). "Tetanus neurotoxin utilizes two sequential membrane interactions for channel formation". The Journal of biological chemistry. 289 (32): 22450–8. PMID 24973217.
  6. ^ Pirazzini, M; Bordin, F; Rossetto, O; Shone, CC; Binz, T; Montecucco, C (16 January 2013). "The thioredoxin reductase-thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals". FEBS letters. 587 (2): 150–5. PMID 23178719.
  7. ^ Pellegrini, LL; O'Connor, V; Lottspeich, F; Betz, H (2 October 1995). "Clostridial neurotoxins compromise the stability of a low energy SNARE complex mediating NSF activation of synaptic vesicle fusion". The EMBO journal. 14 (19): 4705–13. PMID 7588600.
  8. ^ Kumar, Vinay; Abbas, Abul K.; Fausto, Nelson; Aster, Jon (2009-05-28). Robbins and Cotran Pathologic Basis of Disease, Professional Edition: Expert Consult - Online (Robbins Pathology) (Kindle Locations 19359-19360). Elsevier Health. Kindle Edition.
  9. ^ Kanda K; Takano K (February 1983). "Effect of tetanus toxin on the excitatory and the inhibitory post-synaptic potentials in the cat motoneurone". J Physiol. 335: 319–333. PMC 1197355. PMID 6308220.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Schiavo G; Benfenati F; Poulain B; Rossetto O; Polverino de Laureto P; DasGupta BR; Montecucco C (October 29, 1992). "Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin". Nature. 359 (6398): 832–5. doi:10.1038/359832a0. PMID 1331807.{{cite journal}}: CS1 maint: multiple names: authors list (link)

External Links[edit]


This is just some text I wrote and worked with. I don't want to delete it because it has been useful, but you don't need to include it in your review.

Tetanus Neurotoxin (TeNT)[edit]

The breakdown of responsibilities and mechanisms of the heavy (HC) and light chain (LC) of tetanus neurotoxin: The HC assists in binding of TeNT to both the ganglioside receptor and the final receptor. Once TeNT is in the vesicle in the inhibitory interneuron space the HC is also involved in translocation of the LC into the cytoplasm. Then the LC, characterized by zinc endopeptidase activity, inhibits neurotransmission by cleavage of synaptobrevin 1.

Tetanus toxin or TeNT, is composed of a heavy chain (100KDa) and a light chain (50kDa) connected by a disulfide bond. The heavy chain is responsible for neurospecific binding of TeNT to the nerve terminal membrane, endocytosis of the toxin, and translocation of the light chain into the cytosol. The light chain has zinc-dependent endopepdtidase or more specifically matrix metalloproteinase (MMP) activity through which cleaveage of synaptobrevin or VAMP is carried out.[1] TeNT causes tetanus through cleavage of synaptobrevin 2 and not synaptobrevin 1, similarly to botulinum neurotoxin B.[2]

Transportation of TeNT into the nerve is mediated by the heavy chain which reversibly binds to the G1b series of polysialogangliosides on neuron membranes. TeNT then moves with the ganglioside through the lipid membrane to bind to a more specific protein receptor.[3] The receptor with TeNT attached is then endocytosed and goes through retrograde axonal transport through the motor neurons to reach its final target, the inhibitory interneurons of the spinal cord. Translocation of the light chain into the cytosol follows and its subsequent synaptobrevin cleavage.

For the light chain of TeNT to be activated, one atom of zinc must be bound to every molecule of toxin.[4] While the presence of zinc has almost no influence over light chain conformation or stability it is necessary for protease action and is thought to be catalytic.[5] The disulfide bond between the light and heavy chains must also be intact after translocation into the interneuron. The difference between the acidic pH of the vesicle and the neutral pH of the cytosol allows the light chain to refold after translocation, and then it is ready for separation from the heavy chain. When these requirements are met the disulfide bond is reduced, mainly by the NADPH-thioredoxin reductase-thioredoxin redox system.[6] Then the light chain is free to cleave the Gln76-Phe77 bond of synaptobrevin. Cleavage of synaptobrevin affects the stability of the SNARE core by restricting it from entering the low energy conformation, which is the target for NSF binding.[7] This cleavage of synaptobrevin is the final target of TeNT, and even in low doses the neurotoxin will inhibit neurotransmitter exocytosis.

References[edit]

  1. ^ Schiavo, G; Benfenati, F; Poulain, B; Rossetto, O; Polverino de Laureto, P; DasGupta, BR; Montecucco, C (29 October 1992). "Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin". Nature. 359 (6398): 832–5. PMID 1331807.
  2. ^ Rossetto, O; Schiavo, G; Montecucco, C; Poulain, B; Deloye, F; Lozzi, L; Shone, CC (1 December 1994). "SNARE motif and neurotoxins". Nature. 372 (6505): 415–6. PMID 7984234.
  3. ^ Lalli, G; Bohnert, S; Deinhardt, K; Verastegui, C; Schiavo, G (September 2003). "The journey of tetanus and botulinum neurotoxins in neurons". Trends in microbiology. 11 (9): 431–7. PMID 13678859.
  4. ^ Schiavo, G; Poulain, B; Rossetto, O; Benfenati, F; Tauc, L; Montecucco, C (October 1992). "Tetanus toxin is a zinc protein and its inhibition of neurotransmitter release and protease activity depend on zinc". The EMBO journal. 11 (10): 3577–83. PMID 1396558.
  5. ^ De Filippis, V; Vangelista, L; Schiavo, G; Tonello, F; Montecucco, C (1 April 1995). "Structural studies on the zinc-endopeptidase light chain of tetanus neurotoxin". European journal of biochemistry / FEBS. 229 (1): 61–9. PMID 7744050.
  6. ^ Pirazzini, M; Bordin, F; Rossetto, O; Shone, CC; Binz, T; Montecucco, C (16 January 2013). "The thioredoxin reductase-thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals". FEBS letters. 587 (2): 150–5. PMID 23178719.
  7. ^ Pellegrini, LL; O'Connor, V; Lottspeich, F; Betz, H (2 October 1995). "Clostridial neurotoxins compromise the stability of a low energy SNARE complex mediating NSF activation of synaptic vesicle fusion". The EMBO journal. 14 (19): 4705–13. PMID 7588600.

External Links[edit]

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