Animal Toxins and Biological Ion Channels

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

Deadline for manuscript submissions: closed (1 December 2015) | Viewed by 51203

Special Issue Editors

Research School of Biology, Australian National University, Canberra ACT 0200, Australia
Interests: Toxins; ion channels; molecular dynamics; modeling

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Guest Editor
State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, P. R. China
Interests: Scorpion toxins; definsins; potassium channels; peptide engineering; electrophysiology

Special Issue Information

Dear Colleagues,

Ion channels account for the action potential of excitable cells and their malfunction is implicated in many diseases. As such, they form an important drug target. For example, the calcium channel Cav2.2 and the sodium channel Nav1.7 are targets for analgesics, whereas the potassium channel Kv1.3 is a target for immunosuppressants. Many short peptides isolated from venomous animals, such as scorpions, cone snails, and spiders, are potent and specific modulators of certain channels. Those peptides are promising drug scaffolds and understanding their mechanisms-of-action is of critical importance to the development of novel venom-based drugs. This Special Issue aims to bring together studies that advance our understanding of the detailed interactions between venom peptides and ion channels. Both computational and experimental studies are welcome.

Dr. Rong Chen
Dr. Yingliang Wu
Guest Editors

Manuscript Submission Information

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Keywords

  • Toxins
  • Venom peptides
  • Pore blockers
  • Gating modifiers
  • Ion channels
  • Protein-protein interactions
  • Ligand binding

Published Papers (7 papers)

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Research

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3540 KiB  
Article
Activity of Palythoa caribaeorum Venom on Voltage-Gated Ion Channels in Mammalian Superior Cervical Ganglion Neurons
by Fernando Lazcano-Pérez, Héctor Castro, Isabel Arenas, David E. García, Ricardo González-Muñoz and Roberto Arreguín-Espinosa
Toxins 2016, 8(5), 135; https://doi.org/10.3390/toxins8050135 - 5 May 2016
Cited by 13 | Viewed by 5378
Abstract
The Zoanthids are an order of cnidarians whose venoms and toxins have been poorly studied. Palythoa caribaeorum is a zoanthid commonly found around the Mexican coastline. In this study, we tested the activity of P. caribaeorum venom on voltage-gated sodium channel (NaV [...] Read more.
The Zoanthids are an order of cnidarians whose venoms and toxins have been poorly studied. Palythoa caribaeorum is a zoanthid commonly found around the Mexican coastline. In this study, we tested the activity of P. caribaeorum venom on voltage-gated sodium channel (NaV1.7), voltage-gated calcium channel (CaV2.2), the A-type transient outward (IA) and delayed rectifier (IDR) currents of KV channels of the superior cervical ganglion (SCG) neurons of the rat. These results showed that the venom reversibly delays the inactivation process of voltage-gated sodium channels and inhibits voltage-gated calcium and potassium channels in this mammalian model. The compounds responsible for these effects seem to be low molecular weight peptides. Together, these results provide evidence for the potential use of zoanthids as a novel source of cnidarian toxins active on voltage-gated ion channels. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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3680 KiB  
Article
The Scorpion Toxin Analogue BmKTX-D33H as a Potential Kv1.3 Channel-Selective Immunomodulator for Autoimmune Diseases
by Fang Ye, Youtian Hu, Weiwei Yu, Zili Xie, Jun Hu, Zhijian Cao, Wenxin Li and Yingliang Wu
Toxins 2016, 8(4), 115; https://doi.org/10.3390/toxins8040115 - 19 Apr 2016
Cited by 18 | Viewed by 5189
Abstract
The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural [...] Read more.
The Kv1.3 channel-acting scorpion toxins usually adopt the conserved anti-parallel β-sheet domain as the binding interface, but it remains challenging to discover some highly selective Kv1.3 channel-acting toxins. In this work, we investigated the pharmacological profile of the Kv1.3 channel-acting BmKTX-D33H, a structural analogue of the BmKTX scorpion toxin. Interestingly, BmKTX-D33H, with its conserved anti-parallel β-sheet domain as a Kv1.3 channel-interacting interface, exhibited more than 1000-fold selectivity towards the Kv1.3 channel as compared to other K+ channels (including Kv1.1, Kv1.2, Kv1.7, Kv11.1, KCa2.2, KCa2.3, and KCa3.1). As expected, BmKTX-D33H was found to inhibit the cytokine production and proliferation of both Jurkat cells and human T cells in vitro. It also significantly improved the delayed-type hypersensitivity (DTH) responses, an autoreactive T cell-mediated inflammation in rats. Amino acid sequence alignment and structural analysis strongly suggest that the “evolutionary” Gly11 residue of BmKTX-D33H interacts with the turret domain of Kv1 channels; it appears to be a pivotal amino acid residue with regard to the selectivity of BmKTX-D33H towards the Kv1.3 channel (in comparison with the highly homologous scorpion toxins). Together, our data indicate that BmKTX-D33H is a Kv1.3 channel–specific blocker. Finally, the remarkable selectivity of BmKTX-D33H highlights the great potential of evolutionary-guided peptide drug design in future studies. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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2291 KiB  
Article
The Kunitz-Type Protein ShPI-1 Inhibits Serine Proteases and Voltage-Gated Potassium Channels
by Rossana García-Fernández, Steve Peigneur, Tirso Pons, Carlos Alvarez, Lidice González, María A. Chávez and Jan Tytgat
Toxins 2016, 8(4), 110; https://doi.org/10.3390/toxins8040110 - 13 Apr 2016
Cited by 36 | Viewed by 6817
Abstract
The bovine pancreatic trypsin inhibitor (BPTI)-Kunitz-type protein ShPI-1 (UniProt: P31713) is the major protease inhibitor from the sea anemone Stichodactyla helianthus. This molecule is used in biotechnology and has biomedical potential related to its anti-parasitic effect. A pseudo wild-type variant, rShPI-1A, [...] Read more.
The bovine pancreatic trypsin inhibitor (BPTI)-Kunitz-type protein ShPI-1 (UniProt: P31713) is the major protease inhibitor from the sea anemone Stichodactyla helianthus. This molecule is used in biotechnology and has biomedical potential related to its anti-parasitic effect. A pseudo wild-type variant, rShPI-1A, with additional residues at the N- and C-terminal, has a similar three-dimensional structure and comparable trypsin inhibition strength. Further insights into the structure-function relationship of rShPI-1A are required in order to obtain a better understanding of the mechanism of action of this sea anemone peptide. Using enzyme kinetics, we now investigated its activity against other serine proteases. Considering previous reports of bifunctional Kunitz-type proteins from anemones, we also studied the effect of rShPI-1A on voltage-gated potassium (Kv) channels. rShPI-1A binds Kv1.1, Kv1.2, and Kv1.6 channels with IC50 values in the nM range. Hence, ShPI-1 is the first member of the sea anemone type 2 potassium channel toxins family with tight-binding potency against several proteases and different Kv1 channels. In depth sequence analysis and structural comparison of ShPI-1 with similar protease inhibitors and Kv channel toxins showed apparent non-sequence conservation for known key residues. However, we detected two subtle patterns of coordinated amino acid substitutions flanking the conserved cysteine residues at the N- and C-terminal ends. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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3214 KiB  
Article
Analgesic Effects of GpTx-1, PF-04856264 and CNV1014802 in a Mouse Model of NaV1.7-Mediated Pain
by Jennifer R. Deuis, Joshua S. Wingerd, Zoltan Winter, Thomas Durek, Zoltan Dekan, Silmara R. Sousa, Katharina Zimmermann, Tali Hoffmann, Christian Weidner, Mohammed A. Nassar, Paul F. Alewood, Richard J. Lewis and Irina Vetter
Toxins 2016, 8(3), 78; https://doi.org/10.3390/toxins8030078 - 17 Mar 2016
Cited by 92 | Viewed by 11304
Abstract
Loss-of-function mutations of NaV1.7 lead to congenital insensitivity to pain, a rare condition resulting in individuals who are otherwise normal except for the inability to sense pain, making pharmacological inhibition of NaV1.7 a promising therapeutic strategy for the treatment [...] Read more.
Loss-of-function mutations of NaV1.7 lead to congenital insensitivity to pain, a rare condition resulting in individuals who are otherwise normal except for the inability to sense pain, making pharmacological inhibition of NaV1.7 a promising therapeutic strategy for the treatment of pain. We characterized a novel mouse model of NaV1.7-mediated pain based on intraplantar injection of the scorpion toxin OD1, which is suitable for rapid in vivo profiling of NaV1.7 inhibitors. Intraplantar injection of OD1 caused spontaneous pain behaviors, which were reversed by co-injection with NaV1.7 inhibitors and significantly reduced in NaV1.7−/− mice. To validate the use of the model for profiling NaV1.7 inhibitors, we determined the NaV selectivity and tested the efficacy of the reported NaV1.7 inhibitors GpTx-1, PF-04856264 and CNV1014802 (raxatrigine). GpTx-1 selectively inhibited NaV1.7 and was effective when co-administered with OD1, but lacked efficacy when delivered systemically. PF-04856264 state-dependently and selectively inhibited NaV1.7 and significantly reduced OD1-induced spontaneous pain when delivered locally and systemically. CNV1014802 state-dependently, but non-selectively, inhibited NaV channels and was only effective in the OD1 model when delivered systemically. Our novel model of NaV1.7-mediated pain based on intraplantar injection of OD1 is thus suitable for the rapid in vivo characterization of the analgesic efficacy of NaV1.7 inhibitors. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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2792 KiB  
Article
Structure-Activity Relationship of Chlorotoxin-Like Peptides
by Syed Abid Ali, Mehtab Alam, Atiya Abbasi, Eivind A. B. Undheim, Bryan Grieg Fry, Hubert Kalbacher and Wolfgang Voelter
Toxins 2016, 8(2), 36; https://doi.org/10.3390/toxins8020036 - 2 Feb 2016
Cited by 23 | Viewed by 7338
Abstract
Animal venom (e.g., scorpion) is a rich source of various protein and peptide toxins with diverse physio-/pharmaco-logical activities, which generally exert their action via target-specific modulation of different ion channel functions. Scorpion venoms are among the most widely-known source of peptidyl neurotoxins used [...] Read more.
Animal venom (e.g., scorpion) is a rich source of various protein and peptide toxins with diverse physio-/pharmaco-logical activities, which generally exert their action via target-specific modulation of different ion channel functions. Scorpion venoms are among the most widely-known source of peptidyl neurotoxins used for callipering different ion channels, such as; Na+, K+, Ca+, Cl, etc. A new peptide of the chlorotoxin family (i.e., Bs-Tx7) has been isolated, sequenced and synthesized from scorpion Buthus sindicus (family Buthidae) venom. This peptide demonstrates 66% with chlorotoxin (ClTx) and 82% with CFTR channel inhibitor (GaTx1) sequence identities reported from Leiurus quinquestriatus hebraeus venom. The toxin has a molecular mass of 3821 Da and possesses four intra-chain disulphide bonds. Amino acid sequence analysis of Bs-Tx7 revealed the presence of a scissile peptide bond (i.e., Gly-Ile) for human MMP2, whose activity is increased in the case of tumour malignancy. The effect of hMMP2 on Bs-Tx7, or vice versa, observed using the FRET peptide substrate with methoxycoumarin (Mca)/dinitrophenyl (Dnp) as fluorophore/quencher, designed and synthesized to obtain the lowest Km value for this substrate, showed approximately a 60% increase in the activity of hMMP2 upon incubation of Bs-Tx7 with the enzyme at a micromolar concentration (4 µM), indicating the importance of this toxin in diseases associated with decreased MMP2 activity. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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1819 KiB  
Article
Scorpion Toxin, BmP01, Induces Pain by Targeting TRPV1 Channel
by Md Abdul Hakim, Wenbin Jiang, Lei Luo, Bowen Li, Shilong Yang, Yuzhu Song and Ren Lai
Toxins 2015, 7(9), 3671-3687; https://doi.org/10.3390/toxins7093671 - 14 Sep 2015
Cited by 46 | Viewed by 7005
Abstract
The intense pain induced by scorpion sting is a frequent clinical manifestation. To date, there is no established protocol with significant efficacy to alleviate the pain induced by scorpion envenomation. One of the important reasons is that, little information on pain-inducing compound from [...] Read more.
The intense pain induced by scorpion sting is a frequent clinical manifestation. To date, there is no established protocol with significant efficacy to alleviate the pain induced by scorpion envenomation. One of the important reasons is that, little information on pain-inducing compound from scorpion venoms is available. Here, a pain-inducing peptide (BmP01) has been identified and characterized from the venoms of scorpion (Mesobuthus martensii). In an animal model, intraplantar injection of BmP01 in mouse hind paw showed significant acute pain in wild type (WT) mice but not in TRPV1 knock-out (TRPV1 KO) mice during 30 min recording. BmP01 evoked currents in WT dorsal root ganglion (DRG) neurons but had no effect on DRG neurons of TRPV1 KO mice. Furthermore, OPEN ACCESS Toxins 2015, 7 3672 BmP01 evoked currents on TRPV1-expressed HEK293T cells, but not on HEK293T cells without TRPV1. These results suggest that (1) BmP01 is one of the pain-inducing agents in scorpion venoms; and (2) BmP01 induces pain by acting on TRPV1. To our knowledge, this is the first report about a scorpion toxin that produces pain by targeting TRPV1. Identification of a pain-inducing compound may facilitate treating pain induced by scorpion envenomation. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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Review

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3300 KiB  
Review
Computational Studies of Venom Peptides Targeting Potassium Channels
by Rong Chen and Shin-Ho Chung
Toxins 2015, 7(12), 5194-5211; https://doi.org/10.3390/toxins7124877 - 1 Dec 2015
Cited by 16 | Viewed by 7215
Abstract
Small peptides isolated from the venom of animals are potential scaffolds for ion channel drug discovery. This review article mainly focuses on the computational studies that have advanced our understanding of how various toxins interfere with the function of K+ channels. We [...] Read more.
Small peptides isolated from the venom of animals are potential scaffolds for ion channel drug discovery. This review article mainly focuses on the computational studies that have advanced our understanding of how various toxins interfere with the function of K+ channels. We introduce the computational tools available for the study of toxin-channel interactions. We then discuss how these computational tools have been fruitfully applied to elucidate the mechanisms of action of a wide range of venom peptides from scorpions, spiders, and sea anemone. Full article
(This article belongs to the Special Issue Animal Toxins and Biological Ion Channels)
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