Defining the role of post-synaptic α-neurotoxins in paralysis due to snake envenoming in humans |
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| Authors: | Anjana Silva Ben Cristofori-Armstrong Lachlan D Rash Wayne C Hodgson Geoffrey K Isbister |
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| Institution: | 1.Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute,Monash University,Clayton,Australia;2.Faculty of Medicine and Allied Sciences,Rajarata University of Sri Lanka,Saliyapura,Sri Lanka;3.School of Biomedical Sciences,University of Queensland,St. Lucia,Australia;4.Institute of Molecular Bioscience,University of Queensland,St. Lucia,Australia;5.Clinical Toxicology Research Group,University of Newcastle,Callaghan,Australia |
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| 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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