Venoms and Ion Channels

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Animal Venoms".

Deadline for manuscript submissions: closed (15 December 2019) | Viewed by 20766

Special Issue Editor

Toxicology and Pharmacology, Katholieke Universiteit (KU) Leuven, Campus Gasthuisberg, 3000 Leuven, Belgium
Interests: antimicrobial; cytotoxic; worms; acetylcholine receptor; centipede; cone snail; scorpion; voltage-gated ion channel; conotoxin; cancer; wasp; snake; spider; electrophysiology; NMDA; pain; plants; cannabinoid receptor
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Special Issue Information

Dear Colleagues,

Venomous animals are specialized predators that have evolved the most sophisticated peptide chemistry and neuropharmacology for their own biological purposes by producing venoms that contain a structural and functional diversity of neurotoxins. Venoms from marine and terrestrial animals (cone snails, scorpions, spiders, snakes, centipedes, cnidarian, etc.) can be seen as an untapped cocktail of biologically active compounds, being increasingly recognized as new emerging source of peptide-based therapeutics. Ion channels account for the action potential of excitable cells, and their malfunction relates to many diseases. As such, they form an important drug target. Venoms and their components have also shown to be highly selective ligands for a wide range of ion channels and receptors. Therefore, neurotoxins have proved invaluable in unraveling ion channel structure and function. Neurotoxins thus represent interesting lead compounds for the development of, for example, analgesics, anticancer drugs, and drugs for neurological disorders, such as multiple sclerosis, Parkinson’s disease, Alzheimer’s, etc.

This Special Issue of Toxins aims to provide a comprehensive look at venoms and their components and will focus on the mechanism of action, structure–function, and evolution of pharmacological interesting venom components, including but not limited to recent developments relating to the emergence of venoms as an underutilized source of highly evolved bioactive peptides with clinical potential.

Dr. Steve Peigneur
Guest Editor

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Keywords

  • sodium channels
  • potassium channels
  • calcium channels
  • TRP channels
  • acetylcholine receptors
  • cone snail venom peptides
  • spider venom peptides
  • sea anemone toxins
  • scorpion toxins
  • snake toxins

Published Papers (6 papers)

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Research

15 pages, 3203 KiB  
Article
Tb1, a Neurotoxin from Tityus bahiensis Scorpion Venom, Induces Epileptic Seizures by Increasing Glutamate Release
by Emidio Beraldo Neto, Lucas Alves de Freitas, Daniel Carvalho Pimenta, Ivo Lebrun and Ana L. A. Nencioni
Toxins 2020, 12(2), 65; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12020065 - 21 Jan 2020
Cited by 5 | Viewed by 2603
Abstract
Here, we report the neurotoxic effects aroused by the intracerebral injection (in rats) of Tb1, which is a neurotoxin isolated from Tityus bahiensis scorpion venom. Biochemical analyses have demonstrated that this toxin is similar to the gamma toxin from T. serrulatus, which [...] Read more.
Here, we report the neurotoxic effects aroused by the intracerebral injection (in rats) of Tb1, which is a neurotoxin isolated from Tityus bahiensis scorpion venom. Biochemical analyses have demonstrated that this toxin is similar to the gamma toxin from T. serrulatus, which is a β-scorpion toxin that acts on sodium channels, causing the activation process to occur at more hyperpolarized membrane voltages. Male Wistar rats were stereotaxically implanted with intrahippocampal electrodes and cannulas for electroencephalographic recording and the evaluation of amino acid neurotransmitters levels. Treated animals displayed behavioral and electroencephalographic alterations similar to epileptiform activities, such as myoclonus, wet dog shakes, convulsion, strong discharges, neuronal loss, and increased intracerebral levels of glutamate. Scorpion toxins are important pharmacological tools that are widely employed in ion channel dysregulation studies. The current work contributes to the understanding of channelopathies, particularly epilepsy, which may originate, among other events, from dysfunctional sodium channels, which are the main target of the Tb1 toxin. Full article
(This article belongs to the Special Issue Venoms and Ion Channels)
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18 pages, 4781 KiB  
Article
New Insights into the Type II Toxins from the Sea Anemone Heteractis crispa
by Rimma S. Kalina, Steve Peigneur, Elena A. Zelepuga, Pavel S. Dmitrenok, Aleksandra N. Kvetkina, Natalia Y. Kim, Elena V. Leychenko, Jan Tytgat, Emma P. Kozlovskaya, Margarita M. Monastyrnaya and Irina N. Gladkikh
Toxins 2020, 12(1), 44; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12010044 - 10 Jan 2020
Cited by 14 | Viewed by 3767
Abstract
Toxins modulating NaV channels are the most abundant and studied peptide components of sea anemone venom. Three type-II toxins, δ-SHTX-Hcr1f (= RpII), RTX-III, and RTX-VI, were isolated from the sea anemone Heteractis crispa. RTX-VI has been found to be an unusual [...] Read more.
Toxins modulating NaV channels are the most abundant and studied peptide components of sea anemone venom. Three type-II toxins, δ-SHTX-Hcr1f (= RpII), RTX-III, and RTX-VI, were isolated from the sea anemone Heteractis crispa. RTX-VI has been found to be an unusual analog of RTX-III. The electrophysiological effects of Heteractis toxins on nine NaV subtypes were investigated for the first time. Heteractis toxins mainly affect the inactivation of the mammalian NaV channels expressed in the central nervous system (NaV1.1–NaV1.3, NaV1.6) as well as insect and arachnid channels (BgNaV1, VdNaV1). The absence of Arg13 in the RTX-VI structure does not prevent toxin binding with the channel but it has changed its pharmacological profile and potency. According to computer modeling data, the δ-SHTX-Hcr1f binds within the extracellular region of the rNaV1.2 voltage-sensing domain IV and pore-forming domain I through a network of strong interactions, and an additional fixation of the toxin at the channel binding site is carried out through the phospholipid environment. Our data suggest that Heteractis toxins could be used as molecular tools for NaV channel studies or insecticides rather than as pharmacological agents. Full article
(This article belongs to the Special Issue Venoms and Ion Channels)
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20 pages, 6237 KiB  
Article
Anti-Nociceptive and Anti-Inflammation Effect Mechanisms of Mutants of Syb-prII, a Recombinant Neurotoxic Polypeptide
by Chunli Li, Mengqi Ban, Fei Bai, Jianzhao Chen, Xiaoquan Jin and Yongbo Song
Toxins 2019, 11(12), 699; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11120699 - 01 Dec 2019
Cited by 3 | Viewed by 2670
Abstract
Syb-prII, a recombinant neurotoxic polypeptide, has analgesic effects with medicinal value. Previous experiments indicated that Syb-prII displayed strong analgesic activities. Therefore, a series of in vivo and vitro experiments were designed to investigate the analgesic and anti-inflammatory properties and possible mechanisms of Syb-prII. [...] Read more.
Syb-prII, a recombinant neurotoxic polypeptide, has analgesic effects with medicinal value. Previous experiments indicated that Syb-prII displayed strong analgesic activities. Therefore, a series of in vivo and vitro experiments were designed to investigate the analgesic and anti-inflammatory properties and possible mechanisms of Syb-prII. The results showed that administered Syb-prII-1 and Syb-prII-2 (0.5, 1, 2.0 mg/kg, i.v.) to mice significantly reduced the time of licking, biting, or flicking of paws in two phases in formalin-induced inflammatory nociception. Syb-prII-1 inhibited xylene-induced auricular swelling in a dose-dependent manner. The inhibitory effect of 2.0 mg/kg Syb-prII-1 on the ear swelling model was comparable to that of 200 mg/kg aspirin. In addition, the ELISA and Western blot analysis suggested that Syb-prII-1 and Syb-prII-2 may exert an analgesic effect by inhibiting the expression of Nav1.8 and the phosphorylation of ERK, JNK, and P38. Syb-prII-1 markedly suppressed the expression of IL-1β, IL-6, and TNF-α of mice in formalin-induced inflammatory nociception. We used the patch-clamp technique and investigated the effect of Syb-prII-1 on TTX-resistant sodium channel currents in acutely isolated rat DRG neurons. The results showed that Syb-prII-1 can significantly down regulate TTX-resistant sodium channel currents. In conclusion, Syb-prII mutants may alleviate inflammatory pain by significantly inhibiting the expression of Nav1.8, mediated by the phosphorylation of MAPKs and significant inhibition of TTX-resistant sodium channel currents. Full article
(This article belongs to the Special Issue Venoms and Ion Channels)
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21 pages, 6496 KiB  
Article
Venomic, Transcriptomic, and Bioactivity Analyses of Pamphobeteus verdolaga Venom Reveal Complex Disulfide-Rich Peptides That Modulate Calcium Channels
by Sebastian Estrada-Gomez, Fernanda Caldas Cardoso, Leidy Johana Vargas-Muñoz, Juan Carlos Quintana-Castillo, Claudia Marcela Arenas Gómez, Sandy Steffany Pineda and Monica Maria Saldarriaga-Cordoba
Toxins 2019, 11(9), 496; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11090496 - 27 Aug 2019
Cited by 15 | Viewed by 4405
Abstract
Pamphobeteus verdolaga is a recently described Theraphosidae spider from the Andean region of Colombia. Previous reports partially characterized its venom profile. In this study, we conducted a detailed analysis that includes reversed-phase high-performance liquid chromatography (rp-HPLC), calcium influx assays, tandem mass spectrometry analysis [...] Read more.
Pamphobeteus verdolaga is a recently described Theraphosidae spider from the Andean region of Colombia. Previous reports partially characterized its venom profile. In this study, we conducted a detailed analysis that includes reversed-phase high-performance liquid chromatography (rp-HPLC), calcium influx assays, tandem mass spectrometry analysis (tMS/MS), and venom-gland transcriptome. rp-HPLC fractions of P. verdolaga venom showed activity on CaV2.2, CaV3.2, and NaV1.7 ion channels. Active fractions contained several peptides with molecular masses ranging from 3399.4 to 3839.6 Da. The tMS/MS analysis of active fraction displaying the strongest activity to inhibit calcium channels showed sequence fragments similar to one of the translated transcripts detected in the venom-gland transcriptome. The putative peptide of this translated transcript corresponded to a toxin, here named ω-theraphositoxin-Pv3a, a potential ion channel modulator toxin that is, in addition, very similar to other theraphositoxins affecting calcium channels (i.e., ω-theraphotoxin-Asp1a). Additionally, using this holistic approach, we found that P. verdolaga venom is an important source of disulfide-rich proteins expressing at least eight superfamilies. Full article
(This article belongs to the Special Issue Venoms and Ion Channels)
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18 pages, 3304 KiB  
Article
Evaluation of the Spider (Phlogiellus genus) Phlotoxin 1 and Synthetic Variants as Antinociceptive Drug Candidates
by Tânia C. Gonçalves, Pierre Lesport, Sarah Kuylle, Enrico Stura, Justyna Ciolek, Gilles Mourier, Denis Servent, Emmanuel Bourinet, Evelyne Benoit and Nicolas Gilles
Toxins 2019, 11(9), 484; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11090484 - 22 Aug 2019
Cited by 13 | Viewed by 3442
Abstract
Over the two last decades, venom toxins have been explored as alternatives to opioids to treat chronic debilitating pain. At present, approximately 20 potential analgesic toxins, mainly from spider venoms, are known to inhibit with high affinity the NaV1.7 subtype of [...] Read more.
Over the two last decades, venom toxins have been explored as alternatives to opioids to treat chronic debilitating pain. At present, approximately 20 potential analgesic toxins, mainly from spider venoms, are known to inhibit with high affinity the NaV1.7 subtype of voltage-gated sodium (NaV) channels, the most promising genetically validated antinociceptive target identified so far. The present study aimed to consolidate the development of phlotoxin 1 (PhlTx1), a 34-amino acid and 3-disulfide bridge peptide of a Phlogiellus genus spider, as an antinociceptive agent by improving its affinity and selectivity for the human (h) NaV1.7 subtype. The synthetic homologue of PhlTx1 was generated and equilibrated between two conformers on reverse-phase liquid chromatography and exhibited potent analgesic effects in a mouse model of NaV1.7-mediated pain. The effects of PhlTx1 and 8 successfully synthetized alanine-substituted variants were studied (by automated whole-cell patch-clamp electrophysiology) on cell lines stably overexpressing hNaV subtypes, as well as two cardiac targets, the hCaV1.2 and hKV11.1 subtypes of voltage-gated calcium (CaV) and potassium (KV) channels, respectively. PhlTx1 and D7A-PhlTx1 were shown to inhibit hNaV1.1–1.3 and 1.5–1.7 subtypes at hundred nanomolar concentrations, while their affinities for hNaV1.4 and 1.8, hCaV1.2 and hKV11.1 subtypes were over micromolar concentrations. Despite similar analgesic effects in the mouse model of NaV1.7-mediated pain and selectivity profiles, the affinity of D7A-PhlTx1 for the NaV1.7 subtype was at least five times higher than that of the wild-type peptide. Computational modelling was performed to deduce the 3D-structure of PhlTx1 and to suggest the amino acids involved in the efficiency of the molecule. In conclusion, the present structure–activity relationship study of PhlTx1 results in a low improved affinity of the molecule for the NaV1.7 subtype, but without any marked change in the molecule selectivity against the other studied ion channel subtypes. Further experiments are therefore necessary before considering the development of PhlTx1 or synthetic variants as antinociceptive drug candidates. Full article
(This article belongs to the Special Issue Venoms and Ion Channels)
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8 pages, 1029 KiB  
Communication
Inhibition of Kv2.1 Potassium Channels by MiDCA1, A Pre-Synaptically Active PLA2-Type Toxin from Micrurus dumerilii carinicauda Coral Snake Venom
by Niklas Schütter, Yuri Correia Barreto, Vitya Vardanyan, Sönke Hornig, Stephen Hyslop, Sérgio Marangoni, Léa Rodrigues-Simioni, Olaf Pongs and Cháriston André Dal Belo
Toxins 2019, 11(6), 335; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11060335 - 12 Jun 2019
Cited by 8 | Viewed by 3329
Abstract
MiDCA1, a phospholipase A2 (PLA2) neurotoxin isolated from Micrurus dumerilii carinicauda coral snake venom, inhibited a major component of voltage-activated potassium (Kv) currents (41 ± 3% inhibition with 1 μM toxin) in mouse cultured dorsal root ganglion (DRG) neurons. In [...] Read more.
MiDCA1, a phospholipase A2 (PLA2) neurotoxin isolated from Micrurus dumerilii carinicauda coral snake venom, inhibited a major component of voltage-activated potassium (Kv) currents (41 ± 3% inhibition with 1 μM toxin) in mouse cultured dorsal root ganglion (DRG) neurons. In addition, the selective Kv2.1 channel blocker guangxitoxin (GxTx-1E) and MiDCA1 competitively inhibited the outward potassium current in DRG neurons. MiDCA1 (1 µM) reversibly inhibited the Kv2.1 current by 55 ± 8.9% in a Xenopus oocyte heterologous system. The toxin showed selectivity for Kv2.1 channels over all the other Kv channels tested in this study. We propose that Kv2.1 channel blockade by MiDCA1 underlies the toxin’s action on acetylcholine release at mammalian neuromuscular junctions. Full article
(This article belongs to the Special Issue Venoms and Ion Channels)
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