Pain-causing stinging nettle toxins target TMEM233 to modulate NaV1.7 function
oleh: 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
| Format: | Article |
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| Diterbitkan: | Nature Portfolio 2023-04-01 |
Deskripsi
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.