Defining the role of post-synaptic α-neurotoxins in paralysis due to snake envenoming in humans

Anjana Silva, Ben Cristofori-Armstrong, Lachlan D. Rash, Wayne C. Hodgson, Geoffrey K. Isbister

Research output: Contribution to journalArticleResearchpeer-review

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 languageEnglish
Pages (from-to)4465-4478
Number of pages14
JournalCellular and Molecular Life Sciences
Volume75
Issue number23
DOIs
Publication statusPublished - 1 Dec 2018

Keywords

  • Neurotoxicity
  • Nicotinic acetylcholine receptor
  • Paralysis
  • Snakebite
  • α-Neurotoxins

Cite this

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title = "Defining the role of post-synaptic α-neurotoxins in paralysis due to snake envenoming in humans",
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.",
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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 journalArticleResearchpeer-review

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AU - Silva, Anjana

AU - Cristofori-Armstrong, Ben

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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.

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