Spider toxin inhibits gating pore currents underlying periodic paralysis

Roope Männikkö, Zakhar O. Shenkarev, Michael G. Thor, Antonina A. Berkut, Mikhail Yu Myshkin, Alexander S. Paramonov, Dmitrii S. Kulbatskii, Dmitry A. Kuzmin, Marisol Sampedro Castañeda, Louise King, Emma R. Wilson, Ekaterina N. Lyukmanova, Mikhail P. Kirpichnikov, Stephanie Schorge, Frank Bosmans, Michael G. Hanna, Dimitri M. Kullmann, Alexander A. Vassilevski

Research output: Contribution to journalArticle

Abstract

Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel NaV1.4 underlie hypokalemic periodic paralysis (HypoPP) type 2. Gating modifier toxins target ion channels by modifying the function of the VSDs. We tested the hypothesis that these toxins could function as blockers of the pathogenic gating pore currents. We report that a crab spider toxin Hm-3 from Heriaeus melloteei can inhibit gating pore currents due to mutations affecting the second arginine residue in the S4 helix of VSD-I that we have found in patients with HypoPP and describe here. NMR studies show that Hm-3 partitions into micelles through a hydrophobic cluster formed by aromatic residues and reveal complex formation with VSD-I through electrostatic and hydrophobic interactions with the S3b helix and the S3–S4 extracellular loop. Our data identify VSD-I as a specific binding site for neurotoxins on sodium channels. Gating modifier toxins may constitute useful hits for the treatment of HypoPP.

Original languageEnglish (US)
Pages (from-to)4495-4500
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number17
DOIs
StatePublished - Apr 24 2018

Keywords

  • Channelopathy
  • Gating modifier
  • Hypokalemic periodic paralysis
  • Neurotoxin
  • Sodium channel

ASJC Scopus subject areas

  • General

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  • Cite this

    Männikkö, R., Shenkarev, Z. O., Thor, M. G., Berkut, A. A., Myshkin, M. Y., Paramonov, A. S., Kulbatskii, D. S., Kuzmin, D. A., Castañeda, M. S., King, L., Wilson, E. R., Lyukmanova, E. N., Kirpichnikov, M. P., Schorge, S., Bosmans, F., Hanna, M. G., Kullmann, D. M., & Vassilevski, A. A. (2018). Spider toxin inhibits gating pore currents underlying periodic paralysis. Proceedings of the National Academy of Sciences of the United States of America, 115(17), 4495-4500. https://doi.org/10.1073/pnas.1720185115