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Modulatory features of the novel spider toxin μ-TRTX-Df1a isolated from the venom of the spider Davus fasciatus.
Br J Pharmacol. 2017 08; 174(15):2528-2544.BJ

Abstract

BACKGROUND AND PURPOSE

Naturally occurring dysfunction of voltage-gated sodium (NaV) channels results in complex disorders such as chronic pain, making these channels an attractive target for new therapies. In the pursuit of novel NaV modulators, we investigated spider venoms for new inhibitors of NaV channels.

EXPERIMENTAL APPROACH

We used high-throughput screens to identify a NaV modulator in venom of the spider Davus fasciatus. Further characterization of this venom peptide was undertaken using fluorescent and electrophysiological assays, molecular modelling and a rodent pain model.

KEY RESULTS

We identified a potent NaV inhibitor named μ-TRTX-Df1a. This 34-residue peptide fully inhibited responses mediated by NaV 1.7 endogenously expressed in SH-SY5Y cells. Df1a also inhibited voltage-gated calcium (CaV 3) currents but had no activity against the voltage-gated potassium (KV 2) channel. The modelled structure of Df1a, which contains an inhibitor cystine knot motif, is reminiscent of the NaV channel toxin ProTx-I. Electrophysiology revealed that Df1a inhibits all NaV subtypes tested (hNaV 1.1-1.7). Df1a also slowed fast inactivation of NaV 1.1, NaV 1.3 and NaV 1.5 and modified the voltage-dependence of activation and inactivation of most of the NaV subtypes. Df1a preferentially binds to the domain II voltage-sensor and has additional interactions with the voltage sensors domains III and IV, which probably explains its modulatory features. Df1a was analgesic in vivo, reversing the spontaneous pain behaviours induced by the NaV activator OD1.

CONCLUSION AND IMPLICATIONS

μ-TRTX-Df1a shows potential as a new molecule for the development of drugs to treat pain disorders mediated by voltage-gated ion channels.

Authors+Show Affiliations

Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia. School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia. School of Pharmacy, The University of Queensland, Woolloongabba, QLD, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28542706

Citation

Cardoso, Fernanda C., et al. "Modulatory Features of the Novel Spider Toxin μ-TRTX-Df1a Isolated From the Venom of the Spider Davus Fasciatus." British Journal of Pharmacology, vol. 174, no. 15, 2017, pp. 2528-2544.
Cardoso FC, Dekan Z, Smith JJ, et al. Modulatory features of the novel spider toxin μ-TRTX-Df1a isolated from the venom of the spider Davus fasciatus. Br J Pharmacol. 2017;174(15):2528-2544.
Cardoso, F. C., Dekan, Z., Smith, J. J., Deuis, J. R., Vetter, I., Herzig, V., Alewood, P. F., King, G. F., & Lewis, R. J. (2017). Modulatory features of the novel spider toxin μ-TRTX-Df1a isolated from the venom of the spider Davus fasciatus. British Journal of Pharmacology, 174(15), 2528-2544. https://doi.org/10.1111/bph.13865
Cardoso FC, et al. Modulatory Features of the Novel Spider Toxin μ-TRTX-Df1a Isolated From the Venom of the Spider Davus Fasciatus. Br J Pharmacol. 2017;174(15):2528-2544. PubMed PMID: 28542706.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Modulatory features of the novel spider toxin μ-TRTX-Df1a isolated from the venom of the spider Davus fasciatus. AU - Cardoso,Fernanda C, AU - Dekan,Zoltan, AU - Smith,Jennifer J, AU - Deuis,Jennifer R, AU - Vetter,Irina, AU - Herzig,Volker, AU - Alewood,Paul F, AU - King,Glenn F, AU - Lewis,Richard J, Y1 - 2017/06/27/ PY - 2016/04/03/received PY - 2017/05/01/revised PY - 2017/05/02/accepted PY - 2017/5/26/pubmed PY - 2018/1/27/medline PY - 2017/5/26/entrez SP - 2528 EP - 2544 JF - British journal of pharmacology JO - Br. J. Pharmacol. VL - 174 IS - 15 N2 - BACKGROUND AND PURPOSE: Naturally occurring dysfunction of voltage-gated sodium (NaV) channels results in complex disorders such as chronic pain, making these channels an attractive target for new therapies. In the pursuit of novel NaV modulators, we investigated spider venoms for new inhibitors of NaV channels. EXPERIMENTAL APPROACH: We used high-throughput screens to identify a NaV modulator in venom of the spider Davus fasciatus. Further characterization of this venom peptide was undertaken using fluorescent and electrophysiological assays, molecular modelling and a rodent pain model. KEY RESULTS: We identified a potent NaV inhibitor named μ-TRTX-Df1a. This 34-residue peptide fully inhibited responses mediated by NaV 1.7 endogenously expressed in SH-SY5Y cells. Df1a also inhibited voltage-gated calcium (CaV 3) currents but had no activity against the voltage-gated potassium (KV 2) channel. The modelled structure of Df1a, which contains an inhibitor cystine knot motif, is reminiscent of the NaV channel toxin ProTx-I. Electrophysiology revealed that Df1a inhibits all NaV subtypes tested (hNaV 1.1-1.7). Df1a also slowed fast inactivation of NaV 1.1, NaV 1.3 and NaV 1.5 and modified the voltage-dependence of activation and inactivation of most of the NaV subtypes. Df1a preferentially binds to the domain II voltage-sensor and has additional interactions with the voltage sensors domains III and IV, which probably explains its modulatory features. Df1a was analgesic in vivo, reversing the spontaneous pain behaviours induced by the NaV activator OD1. CONCLUSION AND IMPLICATIONS: μ-TRTX-Df1a shows potential as a new molecule for the development of drugs to treat pain disorders mediated by voltage-gated ion channels. SN - 1476-5381 UR - https://www.unboundmedicine.com/medline/citation/28542706/Modulatory_features_of_the_novel_spider_toxin_μ_TRTX_Df1a_isolated_from_the_venom_of_the_spider_Davus_fasciatus_ L2 - https://doi.org/10.1111/bph.13865 DB - PRIME DP - Unbound Medicine ER -