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

doi:10.1073/pnas.1720185115

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 journal › Article › peer-review

13 Scopus citations

Abstract

Gating pore currents through the voltage-sensing domains (VSDs) of the skeletal muscle voltage-gated sodium channel Na_V1.4 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 language	English (US)
Pages (from-to)	4495-4500
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	17
DOIs	https://doi.org/10.1073/pnas.1720185115
State	Published - Apr 24 2018
Externally published	Yes

Keywords

Channelopathy
Gating modifier
Hypokalemic periodic paralysis
Neurotoxin
Sodium channel

ASJC Scopus subject areas

General

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10.1073/pnas.1720185115

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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

Männikkö, R, Shenkarev, ZO, Thor, MG, Berkut, AA, Myshkin, MY, Paramonov, AS, Kulbatskii, DS, Kuzmin, DA, Castañeda, MS, King, L, Wilson, ER, Lyukmanova, EN, Kirpichnikov, MP, Schorge, S, Bosmans, F, Hanna, MG, Kullmann, DM & Vassilevski, AA 2018, 'Spider toxin inhibits gating pore currents underlying periodic paralysis', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 17, pp. 4495-4500. https://doi.org/10.1073/pnas.1720185115

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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.",

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AU - Männikkö, Roope

AU - Shenkarev, Zakhar O.

AU - Thor, Michael G.

AU - Berkut, Antonina A.

AU - Myshkin, Mikhail Yu

AU - Paramonov, Alexander S.

AU - Kulbatskii, Dmitrii S.

AU - Kuzmin, Dmitry A.

AU - Castañeda, Marisol Sampedro

AU - King, Louise

AU - Wilson, Emma R.

AU - Lyukmanova, Ekaterina N.

AU - Kirpichnikov, Mikhail P.

AU - Schorge, Stephanie

AU - Bosmans, Frank

AU - Hanna, Michael G.

AU - Kullmann, Dimitri M.

AU - Vassilevski, Alexander A.

PY - 2018/4/24

Y1 - 2018/4/24

N2 - 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.

AB - 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.

KW - Channelopathy

KW - Gating modifier

KW - Hypokalemic periodic paralysis

KW - Neurotoxin

KW - Sodium channel

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Spider toxin inhibits gating pore currents underlying periodic paralysis

Abstract

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