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Venoms from cone snails and arachnids are a rich source of peptide modulators of voltage-gated sodium (NaV) channels, however relatively few venom-derived peptides with activity at the mammalian NaV1.8 subtype have been isolated. Here, we describe the discovery and functional characterisation of β-theraphotoxin-Eo1a, a peptide from the venom of the Tanzanian black and olive baboon tarantula Encyocratella olivacea that modulates NaV1.8. Eo1a is a 37-residue peptide that increases NaV1.8 peak current (EC50 894 ± 146 nM) and causes a large hyperpolarising shift in both the voltage-dependence of activation (ΔV50–20.5 ± 1.2 mV) and steady-state fast inactivation (ΔV50–15.5 ± 1.8 mV). At a concentration of 10 μM, Eo1a has varying effects on the peak current and channel gating of NaV1.1–NaV1.7, although its activity is most pronounced at NaV1.8. Investigations into the binding site of Eo1a using NaV1.7/NaV1.8 chimeras revealed a critical contribution of the DII S3-S4 extracellular loop of NaV1.8 to toxin activity. Results from this work may form the basis for future studies that lead to the rational design of spider venom-derived peptides with improved potency and selectivity at NaV1.8. [ABSTRACT FROM AUTHOR]

Venoms from cone snails and arachnids are a rich source of peptide modulators of voltage-gated sodium (Na V ) channels, however relatively few venom-derived peptides with activity at the mammalian Na V 1.8 subtype have been isolated. Here, we describe the discovery and functional characterisation of β-theraphotoxin-Eo1a, a peptide from the venom of the Tanzanian black and olive baboon tarantula Encyocratella olivacea that modulates Na V 1.8. Eo1a is a 37-residue peptide that increases Na V 1.8 peak current (EC 50 894 ± 146 nM) and causes a large hyperpolarising shift in both the voltage-dependence of activation (ΔV 50 -20.5 ± 1.2 mV) and steady-state fast inactivation (ΔV 50 -15.5 ± 1.8 mV). At a concentration of 10 μM, Eo1a has varying effects on the peak current and channel gating of Na V 1.1-Na V 1.7, although its activity is most pronounced at Na V 1.8. Investigations into the binding site of Eo1a using Na V 1.7/Na V 1.8 chimeras revealed a critical contribution of the DII S3-S4 extracellular loop of Na V 1.8 to toxin activity. Results from this work may form the basis for future studies that lead to the rational design of spider venom-derived peptides with improved potency and selectivity at Na V 1.8., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Deuis, Ragnarsson, Robinson, Dekan, Chan, Jin, Tran, McMahon, Li, Wood, Cox, King, Herzig and Vetter.)