Inherent fast inactivation particle of Nav channels as a new binding site for a neurotoxin
Neurotoxins derived from animal venoms are indispensable tools for probing the structure and function of voltage-gated sodium (Nav) channels. Utilizing a novel centipede peptide toxin called rpTx1, we show that the "inherent inactivation particle" of Nav channels represents a binding site for a neurotoxin. The toxin comprises two functional domains: one for cell penetration and one for modulating Nav channel activity. After crossing the cell membrane, rpTx1 preferentially binds to and stabilizes the IFMT motif (the conserved core region of the fast inactivation particle in mammalian Nav channels) in the unbound state, preventing this motif from associating with its receptor site and thereby inhibiting the fast inactivation of Nav channels. This competition between rpTx1 and the receptor site for interacting with the IFMT motif may account for the higher activity of rpTx1 on Nav1.8 than on other Nav subtypes, given the weaker relative affinity between the receptor site and the IFMT motif of Nav1.8. Overall, this study should promote the investigation of the intracellular modulation of Nav channels by neurotoxins.
Authors
- Haiyi Chen (ORCID: https://orcid.org/0000-0001-8196-5426)
- Xin Xiao (ORCID: https://orcid.org/0000-0003-1107-6521)
- Xi Zhou (ORCID: https://orcid.org/0000-0001-8491-0201)
- Shuijiao Peng
- Xujun Feng
- Tingjun Hou (ORCID: https://orcid.org/0000-0001-7227-2580)
- Gaoang Wang (ORCID: https://orcid.org/0000-0002-9831-2090)
- Wenxing Wang (ORCID: https://orcid.org/0000-0002-9419-6846)
- Yuxin Si
- Minjuan Lu
- Qing Zhou (ORCID: https://orcid.org/0000-0003-4508-9224)
- Jing Liang Qin (ORCID: https://orcid.org/0000-0002-8302-0968)
- Qianqian Zhang (ORCID: https://orcid.org/0000-0003-3442-4461)
- Zhonghua Liu (ORCID: https://orcid.org/0000-0001-8497-6702)
- Xiaoqing Luo (ORCID: https://orcid.org/0000-0003-3383-0441)
- Xijing He (ORCID: https://orcid.org/0000-0002-0465-5376)
- Yaqi Li (ORCID: https://orcid.org/0000-0002-3010-2599)
- Li Yang (ORCID: https://orcid.org/0000-0003-3922-1823)
- Meijing Wu
- Minzhi Chen (ORCID: https://orcid.org/0009-0004-1362-2412)
- Sen Luo (ORCID: https://orcid.org/0000-0003-3033-854X)
- Qiaoling Xie (ORCID: https://orcid.org/0000-0002-1342-2507)
- Songping Liang
- Weijun Hu
Institutions
- Hangzhou Normal University (CN)
- Hunan Normal University (CN)
- Changsha Normal University (CN)
- Hunan Provincial Center for Disease Control and Prevention (CN)
- Zhejiang Lab (CN)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2025-04-22
- DOI
- https://doi.org/10.1038/s44318-025-00438-9
- Citations
- 4
- Primary Topic
- Ion channel regulation and function
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China