Pain-causing stinging nettle toxins target TMEM233 to modulate Na_V1.7 function

Voltage-gated sodium (Na_V) channels are critical regulators of neuronal excitability and are targeted by many toxins that directly interact with the pore-forming α subunit, typically via extracellular loops of the voltage-sensing domains, or residues forming part of the pore domain. Excelsatoxin A (ExTxA), a pain-causing knottin peptide from the Australian stinging tree Dendrocnide excelsa, is the first reported plant-derived Na_V channel modulating peptide toxin. Here we show that TMEM233, a member of the dispanin family of transmembrane proteins expressed in sensory neurons, is essential for pharmacological activity of ExTxA at Na_V channels, and that co-expression of TMEM233 modulates the gating properties of Na_V1.7. These findings identify TMEM233 as a previously unknown Na_V1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on Na_V channel gating, and provide important insights into the function of Na_V channels in sensory neurons.