Physiology
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.[1] Here, it selectively binds to and is transported into inhibitory neurons via endocytosis.[2] It then leaves the vesicle for the neuron cytosol where it cleaves vesicle associated membrane protein (VAMP) synaptobrevin, which is necessary for membrane fusion of small synaptic vesicles (SSV's).[1] SSV's carry neurotransmitter to the membrane for release, so inhibition of this process blocks neurotransmitter release.
Tetanus toxin specifically blocks the release of the neurotransmitters GABA and glycine from inhibitory neurons. These neurons 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 spastic paralysis seen in tetanus infection.[1]
The tetanus toxin, tetanospasmin, is made up of a heavy chain and a light chain. There are three domains, each of which contribute to the pathophysiology of the toxin.[3] 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.[3]
There are four main steps tetanus’s mechanism of action. Each of them will be explored in more detail below. They are: binding to the neuron, internalization of the toxin, membrane translocation, and cleavage of the target VAMP.
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 the binding to the correct site, recognizing and binding to the correct glycoproteins and glycolipids in the presynaptic membrane. The toxin binds to a site that will be taken into the neuron as an endocytic vesicle that will travel all the way 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.[2]
Internalization
Tetanus toxin is then internalized again via endocytosis, this time in an acidic vesicle.[3] 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.
Membrane Translocation
The toxin then needs a way to get out of the vesicle and into the neuron cytosol in order 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 hydrophobic form.[2] With the hydrophobic patches exposed, the toxin is able to slide into the vesicle membrane. The toxin forms an ion channel in the membrane that is nonspecific for Na+, K+, Ba2+, and Cl- ions.[1] 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.[1] It has been proposed that the channel could allow the light chain (unfolded from the low pH environment) to leave through the toxin pore[4], 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[5].
Enzymatic Target Cleavage
The light chain of the tetanus toxin is a zinc-dependent protease.[6] 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 chelators, the toxin was inhibited, only to be reactivated when the zinc was added back in.[1] The light chain binds to VAMP and cleaves it between Gln76 and Phe77. Without VAMP, vesicles holding the neurotransmitters needed for motor neuron regulation (GABA and Glycine) cannot be released, causing the above mentioned deregulation of motor neurons and muscle tension.
 | This is a user sandbox of Mkrop. You can use it for testing or practicing edits. This is not the sandbox where you should draft your assigned article for a dashboard.wikiedu.org course. To find the right sandbox for your assignment, visit your Dashboard course page and follow the Sandbox Draft link for your assigned article in the My Articles section. |
- ^ a b c d e f Clementi, F.; Fesce, R.; Meldolesi, J.; Valtorta, F.; Pellizzari, Rossella; Rossetto, Ornella; Schiavo, Giampietro; Montecucco, Cesare (1999-02-28). "Tetanus and botulinum neurotoxins: mechanism of action and therapeutic uses". Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences. 354 (1381): 259–268. doi:10.1098/rstb.1999.0377. PMC 1692495. PMID 10212474.
{{cite journal}}: CS1 maint: PMC format (link) - ^ a b c Montecucco, Cesare; Schiavo, Glampietro (1994-07). "Mechanism of action of tetanus and botulinum neurotoxins". Molecular Microbiology. 13 (1): 1–8. doi:10.1111/j.1365-2958.1994.tb00396.x. ISSN 0950-382X.
{{cite journal}}: Check date values in:|date=(help) - ^ a b c Masuyer, Geoffrey; Conrad, Julian; Stenmark, Pål (2017-08-01). "The structure of the tetanus toxin reveals pH-mediated domain dynamics". EMBO reports. 18 (8): 1306–1317. doi:10.15252/embr.201744198. ISSN 1469-221X. PMC 5538627. PMID 28645943.
{{cite journal}}: CS1 maint: PMC format (link) - ^ Beise, Joachim; Hahnen, Josef; Andersen-Beckh, Bettina; Dreyer, Florian (1994-01). "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". Naunyn-Schmiedeberg's Archives of Pharmacology. 349 (1). doi:10.1007/bf00178208. ISSN 0028-1298.
{{cite journal}}: Check date values in:|date=(help) - ^ Cabiaux, Véronique; Lorge, Philippe; Vandenbranden, Michel; Falmagne, Paul; Ruysschaert, J.M. (1985-04). "Tetanus toxin induces fusion and aggregation of lipid vesicles containing phosphatidylinositol at low pH". Biochemical and Biophysical Research Communications. 128 (2): 840–849. doi:10.1016/0006-291x(85)90123-8. ISSN 0006-291X.
{{cite journal}}: Check date values in:|date=(help) - ^ Foran, Patrick; Shone, Clifford C.; Dolly, J. Oliver (1994-12-01). "Differences in the Protease Activities of Tetanus and Botulinum B Toxins Revealed by the Cleavage of Vesicle-Associated Membrane Protein and Various Sized Fragments". Biochemistry. 33 (51): 15365–15374. doi:10.1021/bi00255a017. ISSN 0006-2960.