Editing Tetanus toxin (section)

==Mechanism of action==

The mechanism of TeNT action can be broken down and discussed in these different steps:

;Transport
:# Specific binding in the [[Peripheral nervous system|periphery neurons]]
:# [[Axoplasmic transport|Retrograde axonal transport]] to the CNS [[interneuron|inhibitory interneurons]]
:# [[Transcytosis]] from the axon into the inhibitory interneurons
;Action
:# Temperature- and pH-mediated translocation of the light chain into the cytosol
:# [[Redox|Reduction]] of the disulfide bridge to [[thiol]]s, severing the link between the light and heavy chain
:# Cleavage of synaptobrevin at -Gln<sup>76</sup>-Phe- bond

The first three steps outline the travel of tetanus toxin 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 polysialo[[gangliosides]], similarly to the ''C. botulinum'' neurotoxin. It also binds to another poorly characterized [[Glycophosphatidylinositol|GPI-anchored protein]] receptor more specific to TeNT.<ref name=GPI>{{cite journal | vauthors = Munro P, Kojima H, Dupont JL, Bossu JL, Poulain B, Boquet P | title = High sensitivity of mouse neuronal cells to tetanus toxin requires a GPI-anchored protein | journal = Biochemical and Biophysical Research Communications | volume = 289 | issue = 2 | pages = 623–629 | date = November 2001 | pmid = 11716521 | doi = 10.1006/bbrc.2001.6031 }}</ref><ref name=Gt1b>
{{cite journal | vauthors = Winter A, Ulrich WP, Wetterich F, Weller U, Galla HJ | title = Gangliosides in phospholipid bilayer membranes: interaction with tetanus toxin | journal = Chemistry and Physics of Lipids | volume = 81 | issue = 1 | pages = 21–34 | date = June 1996 | pmid = 9450318 | doi = 10.1016/0009-3084(96)02529-7 }}</ref> Both the ganglioside and the GPI-anchored protein are located in [[lipid microdomain]]s and both are requisite for specific TeNT binding.<ref name="Gt1b" /> 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.<ref name=SV2>{{cite journal | vauthors = Yeh FL, Dong M, Yao J, Tepp WH, Lin G, Johnson EA, Chapman ER | title = SV2 mediates entry of tetanus neurotoxin into central neurons | journal = PLOS Pathogens | volume = 6 | issue = 11 | pages = e1001207 | date = November 2010 | pmid = 21124874 | pmc = 2991259 | doi = 10.1371/journal.ppat.1001207 | doi-access = free }}</ref>

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.<ref name="Time and pH">{{cite journal | vauthors = Pirazzini M, Rossetto O, Bertasio C, Bordin F, Shone CC, Binz T, Montecucco C | title = Time course and temperature dependence of the membrane translocation of tetanus and botulinum neurotoxins C and D in neurons | journal = Biochemical and Biophysical Research Communications | volume = 430 | issue = 1 | pages = 38–42 | date = January 2013 | pmid = 23200837 | doi = 10.1016/j.bbrc.2012.11.048 }}</ref><ref name="Translocation pH">{{cite journal | vauthors = Burns JR, Baldwin MR | title = Tetanus neurotoxin utilizes two sequential membrane interactions for channel formation | journal = The Journal of Biological Chemistry | volume = 289 | issue = 32 | pages = 22450–22458 | date = August 2014 | pmid = 24973217 | pmc = 4139251 | doi = 10.1074/jbc.m114.559302 | doi-access = free }}</ref> Once the toxin has been translocated into the cytosol, chemical reduction of the disulfide bond to separate thiols occurs, mainly by the enzyme [[thioredoxin reductase|NADPH-thioredoxin reductase-thioredoxin]]. The light chain is then free to cleave the Gln76-Phe77 bond of synaptobrevin.<ref name=Thioredoxin>{{cite journal | vauthors = Pirazzini M, Bordin F, Rossetto O, Shone CC, Binz T, Montecucco C | title = The thioredoxin reductase-thioredoxin system is involved in the entry of tetanus and botulinum neurotoxins in the cytosol of nerve terminals | journal = FEBS Letters | volume = 587 | issue = 2 | pages = 150–155 | date = January 2013 | pmid = 23178719 | doi = 10.1016/j.febslet.2012.11.007 | doi-access = free | bibcode = 2013FEBSL.587..150P }}</ref> 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.<ref name="NSF target">{{cite journal | vauthors = Pellegrini LL, O'Connor V, Lottspeich F, Betz H | title = Clostridial neurotoxins compromise the stability of a low energy SNARE complex mediating NSF activation of synaptic vesicle fusion | journal = The EMBO Journal | volume = 14 | issue = 19 | pages = 4705–4713 | date = October 1995 | pmid = 7588600 | pmc = 394567 | doi = 10.1002/j.1460-2075.1995.tb00152.x }}</ref> Synaptobrevin is an integral [[SNARE (protein)|V-SNARE]] necessary for vesicle fusion to membranes. The final target of TeNT is the cleavage of [[synaptobrevin]] and, even in low doses, has the effect of interfering with [[exocytosis]] of [[neurotransmitter]]s from inhibitory [[interneuron]]s. The blockage of the neurotransmitters [[gamma-aminobutyric acid|γ-aminobutyric acid]] (GABA) and [[glycine]] is the direct cause of the physiological effects that TeNT induces. GABA inhibits motor neurons, so by blocking GABA, tetanus toxin causes violent spastic paralysis.<ref>{{cite book | vauthors = Kumar V, Abbas AK, Fausto N, Aster JC | title = Robbins and Cotran Pathologic Basis of Disease | edition = Professional: Expert Consult - Online Kindle | publisher = Elsevier Health }} </ref>  The action of the A-chain also stops the affected neurons from releasing excitatory transmitters,<ref>{{cite journal | vauthors = Kanda K, Takano K | title = Effect of tetanus toxin on the excitatory and the inhibitory post-synaptic potentials in the cat motoneurone | journal = The Journal of Physiology | volume = 335 | pages = 319–333 | date = February 1983 | pmid = 6308220 | pmc = 1197355 | doi = 10.1113/jphysiol.1983.sp014536 }}</ref> by degrading the protein [[synaptobrevin 2]].<ref>{{cite journal | vauthors = Schiavo G, Benfenati F, Poulain B, Rossetto O, Polverino de Laureto P, DasGupta BR, Montecucco C | title = Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin | journal = Nature | volume = 359 | issue = 6398 | pages = 832–835 | date = October 1992 | pmid = 1331807 | doi = 10.1038/359832a0 | s2cid = 4241066 | bibcode = 1992Natur.359..832S }}</ref> The combined consequence is dangerous overactivity in the [[muscle]]s from the smallest sensory stimuli, as the damping of [[motor reflex]]es is inhibited, leading to generalized contractions of the agonist and antagonist musculature, termed a "tetanic spasm".