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

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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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Acknowledgements

This study was funded by a National Health and Medical Research Council—Australia (NHMRC) Senior Research Fellowship (ID: 1061041) and a NHMRC Centres for Research Excellence Grant ID: 1110343. A.S. acknowledges the Monash International Postgraduate Research Scholarship and Monash Graduate Scholarship. B.C.-A. is supported by an Australian Postgraduate Award from the Australian Government. We thank Prof. David Beeson for the human nAChR clones (α-, β-, γ-, δ- and ε-subunits), and Prof Veit Witzemann for the rat nAChR clones (α-, β-, γ-, δ- and ε-subunits).

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  1. Anjana Silva and Ben Cristofori-Armstrong contributed equally to this work.

Authors and Affiliations

  1. Monash Venom Group, Department of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC, 3800, Australia

    Anjana Silva, Wayne C. Hodgson & Geoffrey K. Isbister

  2. Faculty of Medicine and Allied Sciences, Rajarata University of Sri Lanka, Saliyapura, 50008, Sri Lanka

    Anjana Silva

  3. School of Biomedical Sciences, University of Queensland, St. Lucia, QLD, 4072, Australia

    Ben Cristofori-Armstrong & Lachlan D. Rash

  4. Institute of Molecular Bioscience, University of Queensland, St. Lucia, QLD, 4072, Australia

    Ben Cristofori-Armstrong & Lachlan D. Rash

  5. Clinical Toxicology Research Group, University of Newcastle, Callaghan, NSW, 2308, Australia

    Geoffrey K. Isbister

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  1. Anjana Silva
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GKI, WCH, LDR and AS conceived the paper. AS, LDR, BC-A and WCH conducted experiments and analysed data. AS wrote the paper which was improved by all authors. All authors read and approved the final version of the manuscript.

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Correspondence to Lachlan D. Rash, Wayne C. Hodgson or Geoffrey K. Isbister.

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Silva, A., Cristofori-Armstrong, B., Rash, L.D. et al. Defining the role of post-synaptic α-neurotoxins in paralysis due to snake envenoming in humans. Cell. Mol. Life Sci. 75, 4465–4478 (2018). https://doi.org/10.1007/s00018-018-2893-x

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