A venom peptide-induced NaV channel modulation mechanism involving the interplay between fixed channel charges and ionic gradients

Venoms are used by arthropods either to immobilize prey or as defense against predators. Our study focuses on the venom peptide, Ta3a, from the African ant species, Tetramorium africanum and its effects on voltage-gated sodium (Na_V) channels, which are ion channels responsible for the generation of electrical signals in electrically excitable cells, such as neurons. Using the Na_V1.7 isoform as our model Na_V channel we show that Ta3a prolongs single channel active periods with increased open probability and induces non-inactivating whole-cell currents. Ta3a-affected Na_V1.7 channels exhibit a leftward (hyperpolarizing) shift in activation threshold, constitutive activity even in the absence of an activating voltage stimulus, and at cell membrane voltages where channels are normally silent. Current-voltage experiments show that Ta3a shifts the voltage at which Na_V current changes direction (reversal potential) by altering the local ionic concentration of permeant ions (Na⁺) rather than changing the channel's preference for ionic species. We propose a model where Ta3a maintains the positively charged voltage-sensing (S4) domains of the channel in the activated configuration where their electric field is exposed to the extracellular membrane surface to create an ionic bilayer comprising S4 domains and mobile anions (Cl^-). This bilayer has a depolarizing effect on the cell membrane, thus reducing the amount of externally applied voltage required for channel activation.