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

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_V1.8 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_V1.8. Eo1a is a 37-residue peptide that increases Na_V1.8 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 Na_V1.1–Na_V1.7, although its activity is most pronounced at Na_V1.8. Investigations into the binding site of Eo1a using Na_V1.7/Na_V1.8 chimeras revealed a critical contribution of the DII S3-S4 extracellular loop of Na_V1.8 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_V1.8. [ABSTRACT FROM AUTHOR]