@article{acac581071194edd93423b93870a727d,
title = "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.",
keywords = "Urtica dioica, Australia, Pain, Toxins, Biological, Peptides",
author = "Sina Jami and Deuis, {Jennifer R} and Tabea Klasfauseweh and Xiaoyang Cheng and Sergey Kurdyukov and Felicity Chung and Okorokov, {Andrei L} and Shengnan Li and Jiangtao Zhang and Ben Cristofori-Armstrong and Israel, {Mathilde R} and Ju, {Robert J} and Robinson, {Samuel D} and Peng Zhao and Lotten Ragnarsson and {\AA}sa Andersson and Poanna Tran and Vanessa Schendel and McMahon, {Kirsten L} and Tran, {Hue N T} and Chin, {Yanni K-Y} and Yifei Zhu and Junyu Liu and Theo Crawford and Saipriyaa Purushothamvasan and Habib, {Abdella M} and Andersson, {David A} and Rash, {Lachlan D} and Wood, {John N} and Jing Zhao and Stehbens, {Samantha J} and Mehdi Mobli and Andreas Leffler and Daohua Jiang and Cox, {James J} and Waxman, {Stephen G} and Dib-Hajj, {Sulayman D} and {Gregory Neely}, G and Thomas Durek and Irina Vetter",
note = "Funding Information: This work was supported by the University of Queensland Protein Production Facility and the Australian Cancer Research Foundation (ACRF) Cancer Biology Imaging Facility. Financial support was provided by the Australian Research Council (ARC; DP200102377, CE200100012) and the Australian National Health and Medical Research Council (NHMRC) fellowship to I.V. (APP1162503), Project grant (APP1162597) to M.M. and L.D.R., and Medical Research Council grant to J.J.C. and A.L.O. (MR/R011737/1). B.C.A. received funding from an NHMRC CJ Martin Fellowship (APP1162427). J.R.D. received funding through an ARC DECRA fellowship (DE210100422). S.D.H. and S.G.W. were supported by Merit Review Award B9253-C from the U.S. Dept. of Veterans Affairs Rehabilitation Service; The Center for Neuroscience & Regeneration Research is a Collaboration of the Paralyzed Veterans of America with Yale University. M.R.I. and D.A.A. received grants from the UK Medical Research Council (MR/S003428/1, MR/W002426/1). J.J.C., S.L., A.M.H., J.Zhao. and J.N.W. were supported by the Wellcome Trust (200183). A.M.H. receives funding from Qatar University (QUSD-CMED-2018/9-3; QUCG-CMED-19/20-4). We thank Dr. Patrick Walsh and Vincent Truong from Anatomic Inc. for helpful discussions on the gene expression profile of Anatomic Inc. iPSC-derived sensory neurons; Virginia Nink (Queensland Brain Institute, University of Queensland) for expert assistance with flow cytometry; and Prof Jenny Stow and Dr Lin Luo (Institute for Molecular Bioscience, University of Queensland) for provision of FANTOM Riken cDNA plasmids. Funding Information: This work was supported by the University of Queensland Protein Production Facility and the Australian Cancer Research Foundation (ACRF) Cancer Biology Imaging Facility. Financial support was provided by the Australian Research Council (ARC; DP200102377, CE200100012) and the Australian National Health and Medical Research Council (NHMRC) fellowship to I.V. (APP1162503), Project grant (APP1162597) to M.M. and L.D.R., and Medical Research Council grant to J.J.C. and A.L.O. (MR/R011737/1). B.C.A. received funding from an NHMRC CJ Martin Fellowship (APP1162427). J.R.D. received funding through an ARC DECRA fellowship (DE210100422). S.D.H. and S.G.W. were supported by Merit Review Award B9253-C from the U.S. Dept. of Veterans Affairs Rehabilitation Service; The Center for Neuroscience & Regeneration Research is a Collaboration of the Paralyzed Veterans of America with Yale University. M.R.I. and D.A.A. received grants from the UK Medical Research Council (MR/S003428/1, MR/W002426/1). J.J.C., S.L., A.M.H., J.Zhao. and J.N.W. were supported by the Wellcome Trust (200183). A.M.H. receives funding from Qatar University (QUSD-CMED-2018/9-3; QUCG-CMED-19/20-4). We thank Dr. Patrick Walsh and Vincent Truong from Anatomic Inc. for helpful discussions on the gene expression profile of Anatomic Inc. iPSC-derived sensory neurons; Virginia Nink (Queensland Brain Institute, University of Queensland) for expert assistance with flow cytometry; and Prof Jenny Stow and Dr Lin Luo (Institute for Molecular Bioscience, University of Queensland) for provision of FANTOM Riken cDNA plasmids. Publisher Copyright: {\textcopyright} 2023, The Author(s).",
year = "2023",
month = apr,
day = "28",
doi = "10.1038/s41467-023-37963-2",
language = "English",
volume = "14",
pages = "2442",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}