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

Abstract

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 14 Issue 1 Pg. 2442 (04 28 2023) ISSN: 2041-1723 [Electronic] England
• PMID: 37117223 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2023. The Author(s).

Chemical References

• Peptides
• Toxins, Biological
• NAV1.7 Voltage-Gated Sodium Channel

Topics

• Australia
• Pain
• Peptides
• Toxins, Biological
• Urtica dioica
• NAV1.7 Voltage-Gated Sodium Channel (metabolism)