Abstract
Snake venom α-neurotoxins potently inhibit rodent nicotinic acetylcholine receptors (nAChRs), but their activity on human receptors and their role in human paralysis from snakebite remain unclear. We demonstrate that two short-chain α-neurotoxins (SαNTx) functionally inhibit human muscle-type nAChR, but are markedly more reversible than against rat receptors. In contrast, two long-chain α-neurotoxins (LαNTx) show no species differences in potency or reversibility. Mutant studies identified two key residues accounting for this. Proteomic and clinical data suggest that paralysis in human snakebites is not associated with SαNTx, but with LαNTx, such as in cobras. Neuromuscular blockade produced by both subclasses of α-neurotoxins was reversed by antivenom in rat nerve–muscle preparations, supporting its effectiveness in human post-synaptic paralysis.
| Original language | English |
|---|---|
| Pages (from-to) | 4465-4478 |
| Number of pages | 14 |
| Journal | Cellular and Molecular Life Sciences |
| Volume | 75 |
| Issue number | 23 |
| DOIs | |
| Publication status | Published - 1 Dec 2018 |
Keywords
- Neurotoxicity
- Nicotinic acetylcholine receptor
- Paralysis
- Snakebite
- α-Neurotoxins
Cite this
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Defining the role of post-synaptic α-neurotoxins in paralysis due to snake envenoming in humans. / Silva, Anjana; Cristofori-Armstrong, Ben; Rash, Lachlan D.; Hodgson, Wayne C.; Isbister, Geoffrey K.
In: Cellular and Molecular Life Sciences, Vol. 75, No. 23, 01.12.2018, p. 4465-4478.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Defining the role of post-synaptic α-neurotoxins in paralysis due to snake envenoming in humans
AU - Silva, Anjana
AU - Cristofori-Armstrong, Ben
AU - Rash, Lachlan D.
AU - Hodgson, Wayne C.
AU - Isbister, Geoffrey K.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Snake venom α-neurotoxins potently inhibit rodent nicotinic acetylcholine receptors (nAChRs), but their activity on human receptors and their role in human paralysis from snakebite remain unclear. We demonstrate that two short-chain α-neurotoxins (SαNTx) functionally inhibit human muscle-type nAChR, but are markedly more reversible than against rat receptors. In contrast, two long-chain α-neurotoxins (LαNTx) show no species differences in potency or reversibility. Mutant studies identified two key residues accounting for this. Proteomic and clinical data suggest that paralysis in human snakebites is not associated with SαNTx, but with LαNTx, such as in cobras. Neuromuscular blockade produced by both subclasses of α-neurotoxins was reversed by antivenom in rat nerve–muscle preparations, supporting its effectiveness in human post-synaptic paralysis.
AB - Snake venom α-neurotoxins potently inhibit rodent nicotinic acetylcholine receptors (nAChRs), but their activity on human receptors and their role in human paralysis from snakebite remain unclear. We demonstrate that two short-chain α-neurotoxins (SαNTx) functionally inhibit human muscle-type nAChR, but are markedly more reversible than against rat receptors. In contrast, two long-chain α-neurotoxins (LαNTx) show no species differences in potency or reversibility. Mutant studies identified two key residues accounting for this. Proteomic and clinical data suggest that paralysis in human snakebites is not associated with SαNTx, but with LαNTx, such as in cobras. Neuromuscular blockade produced by both subclasses of α-neurotoxins was reversed by antivenom in rat nerve–muscle preparations, supporting its effectiveness in human post-synaptic paralysis.
KW - Neurotoxicity
KW - Nicotinic acetylcholine receptor
KW - Paralysis
KW - Snakebite
KW - α-Neurotoxins
UR - http://www.scopus.com/inward/record.url?scp=85051177689&partnerID=8YFLogxK
U2 - 10.1007/s00018-018-2893-x
DO - 10.1007/s00018-018-2893-x
M3 - Article
VL - 75
SP - 4465
EP - 4478
JO - Cellular and Molecular Life Sciences
JF - Cellular and Molecular Life Sciences
SN - 1420-682X
IS - 23
ER -