Modulatory features of the novel spider toxin μ-TRTX-Df1a isolated from the venom of the spider Davus fasciatus

Cardoso, Fernanda Caldas, Dekan, Zoltan, Smith, Jennifer J., Deuis, Jennifer R., Vetter, Irina, Herzig, Volker, Alewood, Paul F., King, Glenn F and Lewis, Richard 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. doi:10.1111/bph.13865

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Author Cardoso, Fernanda Caldas
Dekan, Zoltan
Smith, Jennifer J.
Deuis, Jennifer R.
Vetter, Irina
Herzig, Volker
Alewood, Paul F.
King, Glenn F
Lewis, Richard J.
Title Modulatory features of the novel spider toxin μ-TRTX-Df1a isolated from the venom of the spider Davus fasciatus
Formatted title
Modulatory features of the novel spider toxin μ-TRTX-Df1a isolated from the venom of the spider Davus fasciatus
Journal name British Journal of Pharmacology   Check publisher's open access policy
ISSN 0007-1188
1476-5381
Publication date 2017-08-01
Year available 2017
Sub-type Article (original research)
DOI 10.1111/bph.13865
Open Access Status File (Author Post-print)
Volume 174
Issue 15
Start page 2528
End page 2544
Total pages 17
Place of publication Chichester, West Sussex United Kingdom
Publisher John Wiley & Sons
Language eng
Formatted abstract
Background and purpose

Naturally occurring dysfunction in 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 modeling 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 NaV1.7 endogenously expressed in SH-SY5Y cells. Df1a also inhibited CaV3 currents but had no activity against KV2. 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 (hNaV1.1–1.7). Df1a also slowed fast inactivation of NaV1.1, NaV1.3 and NaV1.5, and modified the voltage-dependence of activation and inactivation of most NaV subtypes. Df1a preferentially binds to the domain II voltage-sensor and has additional interactions with the voltage sensors domains III and IV, which likely explains its modulatory features. Df1a was analgesic in vivo, reversing the spontaneous pain behaviors induced by the NaV activator OD1.

Conclusion and Implication


μ-TRTX-Df1a shows potential as a new molecule for the development of therapies to treat voltage-gated ion channels mediated pain disorders.
Q-Index Code C1
Institutional Status UQ

 
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Created: Fri, 09 Jun 2017, 13:03:00 EST by Fernanda Caldas Cardoso on behalf of Institute for Molecular Bioscience