A hydrophobic loop of the spider-venom peptide Tl1a drives activity at Na V 1.8

Ashvriya Thapa; Hue Tran; Lotten Ragnarsson; Angelo Keramidas; Volker Herzig; Nina Brinkwirth; Jennifer R Deuis; Irina Vetter

doi:10.1016/j.ejphar.2025.177751

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A hydrophobic loop of the spider-venom peptide Tl1a drives activity at Na V 1.8

Journal article

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A hydrophobic loop of the spider-venom peptide Tl1a drives activity at Na V 1.8

Ashvriya Thapa, Hue Tran, Lotten Ragnarsson, Angelo Keramidas, Volker Herzig, Nina Brinkwirth, Jennifer R Deuis and Irina Vetter

European Journal of Pharmacology, Vol.1001, pp.1-10

2025

DOI: https://doi.org/10.1016/j.ejphar.2025.177751

PMID: 40414593

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Abstract

peptide

venom

Na(V)1.8

Na(V)1.7

voltage-gated sodium channel

spider

Voltage-gated sodium (NaVs) channels are pore-forming transmembrane proteins that regulate the influx of sodium ions across cell membranes. Spider venoms are a rich source of NaV-modulating peptides with high selectivity and potency, making them important tools for understanding NaV structure and function. NaV1.8 is tetrodotoxin-resistant, expressed in the peripheral nervous system and contributes to the propagation of action potentials in nociceptive neurons, making it a potential therapeutic target for pain. We identified Tl1a, a 36 amino acid residue peptide isolated from the crude venom of the Peruvian tarantula species, Thrixopelma longicolli, as a modulator of NaV1.8. Tl1a was synthesized using solid-phase peptide synthesis, and activity was assessed using automated whole-cell patch-clamp recordings. Tl1a inhibited NaV1.8 peak current (IC50 210 nM), delayed the kinetics of activation, inhibited fast inactivation, and caused a persistent current as well as a depolarising shift in the voltage dependence of activation (ΔV1/2 +11 mV). Tl1a inhibited peak current with similar potency at NaV1.5 (IC50 282 nM) and KV2.1 (IC50 156 nM) and was 8-fold selective over the tetrodotoxin-sensitive NaV1.4 (IC50 1769 nM), NaV1.1 (2201 nM) and 6-fold selective over NaV1.7 (IC50 1278 nM) channels. Tl1a analogues with an increased number of charged amino acids in loop 4 of the peptide lost activity at NaV1.8 due to altered interactions with the domain IV S3-S4 extracellular loop. The results of this work contribute to a better understanding of the structure-activity relationships at tetrodotoxin-resistant NaV channels and may be useful for the future rational design of selective NaV1.8 peptide modulators.

Details

Title: A hydrophobic loop of the spider-venom peptide Tl1a drives activity at Na V 1.8
Authors: Ashvriya Thapa - The University of Queensland
Hue Tran - The University of Queensland
Lotten Ragnarsson - The University of Queensland
Angelo Keramidas - The University of Queensland
Volker Herzig - University of the Sunshine Coast, Queensland, School of Science, Technology and Engineering
Nina Brinkwirth - Nanion (Germany)
Jennifer R Deuis (Corresponding Author) - The University of Queensland
Irina Vetter (Corresponding Author) - The University of Queensland
Publication details: European Journal of Pharmacology, Vol.1001, pp.1-10
Publisher: Elsevier BV
Date published: 2025
DOI: 10.1016/j.ejphar.2025.177751
ISSN: 1879-0712
PMID: 40414593
Data Availability: Data will be made available on request.
Grants: Be(e) friendly venomous spiders! Novel biopesticides from arachnid venoms, FT190100482, Australian Research Council (Australia, Canberra) - ARC
Using toxins to manipulate the gating of voltage-gated sodium channels, DE210100422, Australian Research Council (Australia, Canberra) - ARC
The role of ion channels in pain pathways, 1162503, National Health and Medical Research Council (Australia, Canberra) - NHMRC
Organisation Unit: School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 991130082502621
Output Type: Journal article

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