Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes

Akello J Agwa, Steve Peigneur, Chun Yuen Chow, Nicole Lawrence, David J Craik, Jan Tytgat, Glenn F King, Sónia Troeira Henriques, Christina I Schroeder

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Gating modifier toxins (GMTs) are venom-derived peptides isolated from spiders and other venomous creatures and modulate activity of disease-relevant voltage-gated ion channels and are therefore being pursued as therapeutic leads. The amphipathic surface profile of GMTs has prompted the proposal that some GMTs simultaneously bind to the cell membrane and voltage-gated ion channels in a trimolecular complex. Here, we examined whether there is a relationship among spider GMT amphipathicity, membrane binding, and potency or selectivity for voltage-gated sodium (NaV) channels. We used NMR spectroscopy and in silico calculations to examine the structures and physicochemical properties of a panel of nine GMTs and deployed surface plasmon resonance to measure GMT affinity for lipids putatively found in proximity to NaV channels. Electrophysiology was used to quantify GMT activity on NaV1.7, an ion channel linked to chronic pain. Selectivity of the peptides was further examined against a panel of NaV channel subtypes. We show that GMTs adsorb to the outer leaflet of anionic lipid bilayers through electrostatic interactions. We did not observe a direct correlation between GMT amphipathicity and affinity for lipid bilayers. Furthermore, GMT-lipid bilayer interactions did not correlate with potency or selectivity for NaVs. We therefore propose that increased membrane binding is unlikely to improve subtype selectivity and that the conserved amphipathic GMT surface profile is an adaptation that facilitates simultaneous modulation of multiple NaVs.

Original languageEnglish
Pages (from-to)9041-9052
Number of pages12
JournalJournal of Biological Chemistry
Volume293
Issue number23
Early online date27 Apr 2018
DOIs
Publication statusPublished - 8 Jun 2018

Keywords

  • Amino Acid Sequence
  • Animals
  • Arthropod Proteins/chemistry
  • Cell Membrane/drug effects
  • HEK293 Cells
  • Humans
  • Lipid Bilayers/metabolism
  • Models, Molecular
  • NAV1.7 Voltage-Gated Sodium Channel/metabolism
  • Spider Venoms/chemistry
  • Spiders/chemistry
  • Toxins, Biological/chemistry
  • Voltage-Gated Sodium Channel Blockers/chemistry

Cite this

Agwa, A. J., Peigneur, S., Chow, C. Y., Lawrence, N., Craik, D. J., Tytgat, J., King, G. F., Henriques, S. T., & Schroeder, C. I. (2018). Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes. Journal of Biological Chemistry, 293(23), 9041-9052. https://doi.org/10.1074/jbc.RA118.002553