AUTHOR=Deuis Jennifer R. , Ragnarsson Lotten , Robinson Samuel D. , Dekan Zoltan , Chan Lerena , Jin Ai-Hua , Tran Poanna , McMahon Kirsten L. , Li Shengnan , Wood John N. , Cox James J. , King Glenn F. , Herzig Volker , Vetter Irina 

TITLE=The Tarantula Venom Peptide Eo1a Binds to the Domain II S3-S4 Extracellular Loop of Voltage-Gated Sodium Channel NaV1.8 to Enhance Activation

JOURNAL=Frontiers in Pharmacology

VOLUME=12

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.789570

DOI=10.3389/fphar.2021.789570

ISSN=1663-9812

ABSTRACT=<p>Venoms from cone snails and arachnids are a rich source of peptide modulators of voltage-gated sodium (Na<sub>V</sub>) channels, however relatively few venom-derived peptides with activity at the mammalian Na<sub>V</sub>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 <italic>Encyocratella olivacea</italic> that modulates Na<sub>V</sub>1.8. Eo1a is a 37-residue peptide that increases Na<sub>V</sub>1.8 peak current (EC<sub>50</sub> 894 ± 146 nM) and causes a large hyperpolarising shift in both the voltage-dependence of activation (ΔV<sub>50</sub>–20.5 ± 1.2 mV) and steady-state fast inactivation (ΔV<sub>50</sub>–15.5 ± 1.8 mV). At a concentration of 10 μM, Eo1a has varying effects on the peak current and channel gating of Na<sub>V</sub>1.1–Na<sub>V</sub>1.7, although its activity is most pronounced at Na<sub>V</sub>1.8. Investigations into the binding site of Eo1a using Na<sub>V</sub>1.7/Na<sub>V</sub>1.8 chimeras revealed a critical contribution of the DII S3-S4 extracellular loop of Na<sub>V</sub>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<sub>V</sub>1.8.</p>