Modulatory features of the novel spider toxin μ‐TRTX‐Df1a isolated from the venom of the spider Davus fasciatus. (27th June 2017)

• Record Type: Journal Article
• Authors: Cardoso, Fernanda C; Dekan, Zoltan; Smith, Jennifer J; Deuis, Jennifer R; Vetter, Irina; Herzig, Volker; Alewood, Paul F; King, Glenn F; Lewis, Richard J
• Is Part Of: British journal of pharmacology. Volume 174:Number 15(2017)
• Page Start: 2528
• Page End: 2544
• Publication Date: 2017-06-27
• Subjects: Pharmacology -- Periodicals; Chemotherapy -- Periodicals; Drug Therapy -- Periodicals; Pharmacology -- Periodicals; 615.1
• DOI: 10.1111/bph.13865
• Languages: English
• ISSNs: 0007-1188

Abstract

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.