Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function.

Voltage-gated sodium (NaV) 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 NaV 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 NaV channels, and that co-expression of TMEM233 modulates the gating properties of NaV1.7. These findings identify TMEM233 as a previously unknown NaV1.7-interacting protein, position TMEM233 and the dispanins as accessory proteins that are indispensable for toxin-mediated effects on NaV channel gating, and provide important insights into the function of NaV channels in sensory neurons. © 2023. The Author(s).

Citation

Sina Jami, Jennifer R Deuis, Tabea Klasfauseweh, Xiaoyang Cheng, Sergey Kurdyukov, Felicity Chung, Andrei L Okorokov, Shengnan Li, Jiangtao Zhang, Ben Cristofori-Armstrong, Mathilde R Israel, Robert J Ju, Samuel D Robinson, Peng Zhao, Lotten Ragnarsson, Åsa Andersson, Poanna Tran, Vanessa Schendel, Kirsten L McMahon, Hue N T Tran, Yanni K-Y Chin, Yifei Zhu, Junyu Liu, Theo Crawford, Saipriyaa Purushothamvasan, Abdella M Habib, David A Andersson, Lachlan D Rash, John N Wood, Jing Zhao, Samantha J Stehbens, Mehdi Mobli, Andreas Leffler, Daohua Jiang, James J Cox, Stephen G Waxman, Sulayman D Dib-Hajj, G Gregory Neely, Thomas Durek, Irina Vetter. Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function. Nature communications. 2023 Apr 28;14(1):2442

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PMID: 37117223

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