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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.

SUBMITTER: Jami S 

PROVIDER: S-EPMC10147923 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Pain-causing stinging nettle toxins target TMEM233 to modulate Na<sub>V</sub>1.7 function.

Jami Sina S   Deuis Jennifer R JR   Klasfauseweh Tabea T   Cheng Xiaoyang X   Kurdyukov Sergey S   Chung Felicity F   Okorokov Andrei L AL   Li Shengnan S   Zhang Jiangtao J   Cristofori-Armstrong Ben B   Israel Mathilde R MR   Ju Robert J RJ   Robinson Samuel D SD   Zhao Peng P   Ragnarsson Lotten L   Andersson Åsa Å   Tran Poanna P   Schendel Vanessa V   McMahon Kirsten L KL   Tran Hue N T HNT   Chin Yanni K-Y YK   Zhu Yifei Y   Liu Junyu J   Crawford Theo T   Purushothamvasan Saipriyaa S   Habib Abdella M AM   Andersson David A DA   Rash Lachlan D LD   Wood John N JN   Zhao Jing J   Stehbens Samantha J SJ   Mobli Mehdi M   Leffler Andreas A   Jiang Daohua D   Cox James J JJ   Waxman Stephen G SG   Dib-Hajj Sulayman D SD   Neely G Gregory GG   Durek Thomas T   Vetter Irina I  

Nature communications 20230428 1

Voltage-gated sodium (Na<sub>V</sub>) 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<sub>V</sub> channel modulating peptide toxin. Here we sh  ...[more]

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