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Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes.
J Biol Chem. 2018 06 08; 293(23):9041-9052.JB

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.

Authors+Show Affiliations

From the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia and.Laboratory of Toxicology and Pharmacology, University of Leuven (KU Leuven), 3000 Leuven, Belgium.From the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia and.From the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia and.From the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia and.Laboratory of Toxicology and Pharmacology, University of Leuven (KU Leuven), 3000 Leuven, Belgium.From the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia and.From the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia and.From the Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia and c.schroeder@imb.uq.edu.au.

Pub Type(s)

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

Language

eng

PubMed ID

29703751

Citation

Agwa, Akello J., et al. "Gating Modifier Toxins Isolated From Spider Venom: Modulation of Voltage-gated Sodium Channels and the Role of Lipid Membranes." The Journal of Biological Chemistry, vol. 293, no. 23, 2018, pp. 9041-9052.
Agwa AJ, Peigneur S, Chow CY, et al. Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes. J Biol Chem. 2018;293(23):9041-9052.
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. The Journal of Biological Chemistry, 293(23), 9041-9052. https://doi.org/10.1074/jbc.RA118.002553
Agwa AJ, et al. Gating Modifier Toxins Isolated From Spider Venom: Modulation of Voltage-gated Sodium Channels and the Role of Lipid Membranes. J Biol Chem. 2018 06 8;293(23):9041-9052. PubMed PMID: 29703751.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes. AU - Agwa,Akello J, AU - Peigneur,Steve, AU - Chow,Chun Yuen, AU - Lawrence,Nicole, AU - Craik,David J, AU - Tytgat,Jan, AU - King,Glenn F, AU - Henriques,Sónia Troeira, AU - Schroeder,Christina I, Y1 - 2018/04/27/ PY - 2018/02/25/received PY - 2018/04/25/revised PY - 2018/4/29/pubmed PY - 2019/1/23/medline PY - 2018/4/29/entrez KW - amphipathic surface KW - disulfide-rich peptides KW - gating modifier toxin KW - lipid-protein interaction KW - oxidative folding KW - pain KW - peptides KW - pharmacology KW - rational drug design KW - sodium channel KW - tarantula venom KW - toxin KW - voltage sensor domain SP - 9041 EP - 9052 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 293 IS - 23 N2 - 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. SN - 1083-351X UR - https://www.unboundmedicine.com/medline/citation/29703751/Gating_modifier_toxins_isolated_from_spider_venom:_Modulation_of_voltage_gated_sodium_channels_and_the_role_of_lipid_membranes_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=29703751 DB - PRIME DP - Unbound Medicine ER -