Editing Tetanus (section)

== Pathophysiology ==
[[File:Neurotransmitter vesicle before and after exposure to Tetanus Toxin.jpg|thumb|upright=1.4|A neurotransmitter-filled vesicle before and after exposure to the tetanus toxin. The cleavage of the VAMP protein by the toxin inhibits vesicle fusion and neurotransmitter release into the synapse.]]
Tetanus [[neurotoxin]] (TeNT) binds to the presynaptic membrane of the [[neuromuscular junction]], is internalized, and is transported back through the axon until it reaches the [[central nervous system]].<ref name=":0">{{cite journal | vauthors = Pellizzari R, Rossetto O, Schiavo G, Montecucco C | title = Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 354 | issue = 1381 | pages = 259–68 | date = February 1999 | pmid = 10212474 | pmc = 1692495 | doi = 10.1098/rstb.1999.0377 | veditors = Clementi F, Fesce R }}</ref> Here, it selectively binds to and is transported into inhibitory neurons via [[endocytosis]].<ref name=":1">{{cite journal | vauthors = Montecucco C, Schiavo G, Meldolesi J, Valtorta F | title = Mechanism of action of tetanus and botulinum neurotoxins | journal = Molecular Microbiology | volume = 13 | issue = 1 | pages = 1–8 | date = July 1994 | pmid = 7527117 | doi = 10.1111/j.1365-2958.1994.tb00396.x | s2cid = 45069991 | doi-access = free }}</ref> It then leaves the vesicle for the neuron cytosol, where it cleaves [[Vesicle-associated membrane protein|vesicle associated membrane protein]] (VAMP) [[synaptobrevin]], which is necessary for membrane fusion of small synaptic vesicles (SSV's).<ref name=":0" /> SSV's carry [[neurotransmitter]] to the membrane for release, so inhibition of this process blocks neurotransmitter release.<ref>{{Cite journal |last=Jung |first=Jae Hoon |date=2019-05-31 |title=Synaptic Vesicles Having Large Contact Areas with the Presynaptic Membrane are Preferentially Hemifused at Active Zones of Frog Neuromuscular Junctions Fixed during Synaptic Activity |journal=International Journal of Molecular Sciences |volume=20 |issue=11 |pages=2692 |doi=10.3390/ijms20112692 |doi-access=free |issn=1422-0067 |pmc=6600287 |pmid=31159267}}</ref>

Tetanus toxin specifically blocks the release of the neurotransmitters [[Gamma-Aminobutyric acid|GABA]] and [[glycine]] from inhibitory neurons. These neurotransmitters keep overactive motor neurons from firing and also play a role in the relaxation of muscles after contraction. When inhibitory neurons are unable to release their neurotransmitters, motor neurons fire out of control, and muscles have difficulty relaxing. This causes the muscle spasms and [[Spasticity|spastic paralysis]] seen in tetanus infection.<ref name=":0" />

The tetanus toxin, [[tetanospasmin]], is made up of a heavy chain and a light chain. There are three domains, each of which contributes to the pathophysiology of the toxin.<ref name=":2">{{cite journal | vauthors = Masuyer G, Conrad J, Stenmark P | title = The structure of the tetanus toxin reveals pH-mediated domain dynamics | journal = EMBO Reports | volume = 18 | issue = 8 | pages = 1306–1317 | date = August 2017 | pmid = 28645943 | pmc = 5538627 | doi = 10.15252/embr.201744198 }}</ref> The heavy chain has two of the domains. The N-terminal side of the heavy chain helps with membrane translocation, and the C-terminal side helps the toxin locate the specific receptor site on the correct neuron. The light chain domain cleaves the VAMP protein once it arrives in the inhibitory neuron cytosol.<ref name=":2" />

There are four main steps in tetanus's mechanism of action: binding to the neuron, internalization of the toxin, membrane translocation, and cleavage of the target VAMP.<ref>{{Citation |last=Plumlee |first=Konnie H. |title=Chapter 18 - Biotoxins |date=2004-01-01 |url=https://www.sciencedirect.com/science/article/pii/B032301125X500212 |work=Clinical Veterinary Toxicology |pages=98–116 |editor-last=Plumlee |editor-first=Konnie H. |place=Saint Louis |publisher=Mosby |language=en |isbn=978-0-323-01125-9 |access-date=2022-06-21}}</ref>

=== Neurospecific binding ===

The toxin travels from the wound site to the [[neuromuscular junction]] through the bloodstream, where it binds to the [[presynaptic membrane]] of a [[motor neuron]]. The heavy chain C-terminal domain aids in binding to the correct site, recognizing and binding to the correct [[glycoprotein]]s and [[glycolipid]]s in the presynaptic membrane. The toxin binds to a site that will be taken into the neuron as an [[Endocytosis|endocytic vesicle]] that will travel down the axon, past the cell body, and down the dendrites to the dendritic terminal at the spine and central nervous system. Here, it will be released into the [[synaptic cleft]], and allowed to bind with the presynaptic membrane of inhibitory neurons in a similar manner seen with the binding to the motor neuron.<ref name=":1" />

=== Internalization ===

Tetanus toxin is then internalized again via [[endocytosis]], this time, in an acidic vesicle.<ref name=":2" /> In a mechanism not well understood, [[depolarization]] caused by the firing of the inhibitory neuron causes the toxin to be pulled into the neuron inside vesicles.{{citation needed|date=June 2021}}

=== Membrane translocation ===

The toxin then needs a way to get out of the vesicle and into the neuron cytosol for it to act on its target. The low pH of the vesicle lumen causes a conformational change in the toxin, shifting it from a water-soluble form to a [[Hydrophobe|hydrophobic]] form.<ref name=":1" /> With the hydrophobic patches exposed, the toxin can slide into the vesicle membrane. The toxin forms an [[ion channel]] in the membrane that is nonspecific for Na<sup>+</sup>, K<sup>+</sup>, Ca<sup>2+</sup>, and Cl<sup>−</sup> ions.<ref name=":0" /> There is a consensus among experts that this new channel is involved in the translocation of the toxin's light chain from the inside of the vesicle to the neuron cytosol, but the mechanism is not well understood or agreed upon. It has been proposed that the channel could allow the light chain (unfolded from the low pH environment) to leave through the toxin pore,<ref>{{cite journal | vauthors = Beise J, Hahnen J, Andersen-Beckh B, Dreyer F | title = Pore formation by tetanus toxin, its chain, and fragments in neuronal membranes and evaluation of the underlying motifs in the structure of the toxin molecule | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 349 | issue = 1 | pages = 66–73 | date = January 1994 | pmid = 8139702 | doi = 10.1007/BF00178208 | s2cid = 9398335 }}</ref> or that the pore could alter the [[electrochemical gradient]] enough, by letting in or out ions, to cause osmotic lysis of the vesicle, spilling the vesicle's contents.<ref>{{cite journal | vauthors = Cabiaux V, Lorge P, Vandenbranden M, Falmagne P, Ruysschaert JM | title = Tetanus toxin induces fusion and aggregation of lipid vesicles containing phosphatidylinositol at low pH | journal = Biochemical and Biophysical Research Communications | volume = 128 | issue = 2 | pages = 840–9 | date = April 1985 | pmid = 3994725 | doi = 10.1016/0006-291X(85)90123-8 }}</ref>

=== Enzymatic target cleavage ===

The light chain of the tetanus toxin is zinc-dependent [[protease]]. It shares a common zinc protease motif (His-Glu-Xaa-Xaa-His) that researchers hypothesized was essential for target cleavage until this was more recently confirmed by experiment: when all zinc was removed from the neuron with heavy metal [[Chelation|chelators]], the toxin was inhibited, only to be reactivated when the zinc was added back in.<ref name=":0" /> The light chain binds to VAMP, and cleaves it between Gln<sup>76</sup> and Phe<sup>77</sup>. Without VAMP, vesicles holding the neurotransmitters needed for motor neuron regulation ([[Gamma-Aminobutyric acid|GABA]] and glycine) cannot be released, causing the above-mentioned deregulation of motor neurons and muscle tension.<ref>{{cite journal | vauthors = Foran P, Shone CC, Dolly JO | title = Differences in the protease activities of tetanus and botulinum B toxins revealed by the cleavage of vesicle-associated membrane protein and various sized fragments | journal = Biochemistry | volume = 33 | issue = 51 | pages = 15365–74 | date = December 1994 | pmid = 7803399 | doi = 10.1021/bi00255a017 }}</ref>