The Dragon’s Paralysing Spell: Evidence of Sodium and Calcium Ion Channel Binding Neurotoxins in Helodermatid and Varanid Lizard Venoms
Bites from helodermatid lizards can cause pain, paresthesia, paralysis, and tachycardia, as well as other symptoms consistent with neurotoxicity. Furthermore, in vitro studies have shown that <i>Heloderma horridum</i> venom inhibits ion flux and blocks the electrical stimulation of skele...
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MDPI AG
2021-08-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/13/8/549 |
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| author | James S. Dobson Richard J. Harris Christina N. Zdenek Tam Huynh Wayne C. Hodgson Frank Bosmans Rudy Fourmy Aude Violette Bryan G. Fry |
| author_facet | James S. Dobson Richard J. Harris Christina N. Zdenek Tam Huynh Wayne C. Hodgson Frank Bosmans Rudy Fourmy Aude Violette Bryan G. Fry |
| author_sort | James S. Dobson |
| collection | DOAJ |
| description | Bites from helodermatid lizards can cause pain, paresthesia, paralysis, and tachycardia, as well as other symptoms consistent with neurotoxicity. Furthermore, in vitro studies have shown that <i>Heloderma horridum</i> venom inhibits ion flux and blocks the electrical stimulation of skeletal muscles. Helodermatids have long been considered the only venomous lizards, but a large body of robust evidence has demonstrated venom to be a basal trait of Anguimorpha. This clade includes varanid lizards, whose bites have been reported to cause anticoagulation, pain, and occasionally paralysis and tachycardia. Despite the evolutionary novelty of these lizard venoms, their neuromuscular targets have yet to be identified, even for the iconic helodermatid lizards. Therefore, to fill this knowledge gap, the venoms of three <i>Heloderma</i> species (<i>H. exasperatum</i>, <i>H. horridum</i> and <i>H. suspectum</i>) and two <i>Varanus</i> species (<i>V. salvadorii</i> and <i>V. varius</i>) were investigated using <i>Gallus gallus</i> chick biventer cervicis nerve–muscle preparations and biolayer interferometry assays for binding to mammalian ion channels. Incubation with <i>Heloderma</i> venoms caused the reduction in nerve-mediated muscle twitches post initial response of avian skeletal muscle tissue preparation assays suggesting voltage-gated sodium (Na<sub>V</sub>) channel binding. Congruent with the flaccid paralysis inducing blockage of electrical stimulation in the skeletal muscle preparations, the biolayer interferometry tests with <i>Heloderma suspectum</i> venom revealed binding to the S3–S4 loop within voltage-sensing domain IV of the skeletal muscle channel subtype, Na<sub>V</sub>1.4. Consistent with tachycardia reported in clinical cases, the venom also bound to voltage-sensing domain IV of the cardiac smooth muscle calcium channel, Ca<sub>V</sub>1.2. While <i>Varanus varius</i> venom did not have discernable effects in the avian tissue preparation assay at the concentration tested, in the biointerferometry assay both <i>V. varius</i> and <i>V. salvadorii</i> bound to voltage-sensing domain IV of both Na<sub>V</sub>1.4 and Ca<sub>V</sub>1.2, similar to <i>H. suspectum</i> venom. The ability of varanid venoms to bind to mammalian ion channels but not to the avian tissue preparation suggests prey-selective actions, as did the differential potency within the <i>Heloderma</i> venoms for avian versus mammalian pathophysiological targets. This study thus presents the detailed characterization of <i>Heloderma</i> venom ion channel neurotoxicity and offers the first evidence of varanid lizard venom neurotoxicity. In addition, the data not only provide information useful to understanding the clinical effects produced by envenomations, but also reveal their utility as physiological probes, and underscore the potential utility of neglected venomous lineages in the drug design and development pipeline. |
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| series | Toxins |
| spelling | doaj.art-f2d6df6865f14b40ac3515ead073d67f2023-11-22T10:04:33ZengMDPI AGToxins2072-66512021-08-0113854910.3390/toxins13080549The Dragon’s Paralysing Spell: Evidence of Sodium and Calcium Ion Channel Binding Neurotoxins in Helodermatid and Varanid Lizard VenomsJames S. Dobson0Richard J. Harris1Christina N. Zdenek2Tam Huynh3Wayne C. Hodgson4Frank Bosmans5Rudy Fourmy6Aude Violette7Bryan G. Fry8Venom Evolution Lab, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, AustraliaVenom Evolution Lab, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, AustraliaVenom Evolution Lab, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, AustraliaDepartment of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaDepartment of Pharmacology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, AustraliaDepartment of Basic and Applied Medical Sciences, Ghent University, 9000 Ghent, BelgiumAlphabiotoxine Laboratory sprl, Barberie 15, 7911 Montroeul-au-Bois, BelgiumAlphabiotoxine Laboratory sprl, Barberie 15, 7911 Montroeul-au-Bois, BelgiumVenom Evolution Lab, School of Biological Sciences, University of Queensland, St. Lucia, QLD 4072, AustraliaBites from helodermatid lizards can cause pain, paresthesia, paralysis, and tachycardia, as well as other symptoms consistent with neurotoxicity. Furthermore, in vitro studies have shown that <i>Heloderma horridum</i> venom inhibits ion flux and blocks the electrical stimulation of skeletal muscles. Helodermatids have long been considered the only venomous lizards, but a large body of robust evidence has demonstrated venom to be a basal trait of Anguimorpha. This clade includes varanid lizards, whose bites have been reported to cause anticoagulation, pain, and occasionally paralysis and tachycardia. Despite the evolutionary novelty of these lizard venoms, their neuromuscular targets have yet to be identified, even for the iconic helodermatid lizards. Therefore, to fill this knowledge gap, the venoms of three <i>Heloderma</i> species (<i>H. exasperatum</i>, <i>H. horridum</i> and <i>H. suspectum</i>) and two <i>Varanus</i> species (<i>V. salvadorii</i> and <i>V. varius</i>) were investigated using <i>Gallus gallus</i> chick biventer cervicis nerve–muscle preparations and biolayer interferometry assays for binding to mammalian ion channels. Incubation with <i>Heloderma</i> venoms caused the reduction in nerve-mediated muscle twitches post initial response of avian skeletal muscle tissue preparation assays suggesting voltage-gated sodium (Na<sub>V</sub>) channel binding. Congruent with the flaccid paralysis inducing blockage of electrical stimulation in the skeletal muscle preparations, the biolayer interferometry tests with <i>Heloderma suspectum</i> venom revealed binding to the S3–S4 loop within voltage-sensing domain IV of the skeletal muscle channel subtype, Na<sub>V</sub>1.4. Consistent with tachycardia reported in clinical cases, the venom also bound to voltage-sensing domain IV of the cardiac smooth muscle calcium channel, Ca<sub>V</sub>1.2. While <i>Varanus varius</i> venom did not have discernable effects in the avian tissue preparation assay at the concentration tested, in the biointerferometry assay both <i>V. varius</i> and <i>V. salvadorii</i> bound to voltage-sensing domain IV of both Na<sub>V</sub>1.4 and Ca<sub>V</sub>1.2, similar to <i>H. suspectum</i> venom. The ability of varanid venoms to bind to mammalian ion channels but not to the avian tissue preparation suggests prey-selective actions, as did the differential potency within the <i>Heloderma</i> venoms for avian versus mammalian pathophysiological targets. This study thus presents the detailed characterization of <i>Heloderma</i> venom ion channel neurotoxicity and offers the first evidence of varanid lizard venom neurotoxicity. In addition, the data not only provide information useful to understanding the clinical effects produced by envenomations, but also reveal their utility as physiological probes, and underscore the potential utility of neglected venomous lineages in the drug design and development pipeline.https://www.mdpi.com/2072-6651/13/8/549<i>Heloderma</i><i>Varanus</i>venomToxicoferaneurotoxicsodium channel |
| spellingShingle | James S. Dobson Richard J. Harris Christina N. Zdenek Tam Huynh Wayne C. Hodgson Frank Bosmans Rudy Fourmy Aude Violette Bryan G. Fry The Dragon’s Paralysing Spell: Evidence of Sodium and Calcium Ion Channel Binding Neurotoxins in Helodermatid and Varanid Lizard Venoms Toxins <i>Heloderma</i> <i>Varanus</i> venom Toxicofera neurotoxic sodium channel |
| title | The Dragon’s Paralysing Spell: Evidence of Sodium and Calcium Ion Channel Binding Neurotoxins in Helodermatid and Varanid Lizard Venoms |
| title_full | The Dragon’s Paralysing Spell: Evidence of Sodium and Calcium Ion Channel Binding Neurotoxins in Helodermatid and Varanid Lizard Venoms |
| title_fullStr | The Dragon’s Paralysing Spell: Evidence of Sodium and Calcium Ion Channel Binding Neurotoxins in Helodermatid and Varanid Lizard Venoms |
| title_full_unstemmed | The Dragon’s Paralysing Spell: Evidence of Sodium and Calcium Ion Channel Binding Neurotoxins in Helodermatid and Varanid Lizard Venoms |
| title_short | The Dragon’s Paralysing Spell: Evidence of Sodium and Calcium Ion Channel Binding Neurotoxins in Helodermatid and Varanid Lizard Venoms |
| title_sort | dragon s paralysing spell evidence of sodium and calcium ion channel binding neurotoxins in helodermatid and varanid lizard venoms |
| topic | <i>Heloderma</i> <i>Varanus</i> venom Toxicofera neurotoxic sodium channel |
| url | https://www.mdpi.com/2072-6651/13/8/549 |
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