UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Spider toxin inhibits gating pore currents underlying periodic paralysis

Männikkö, R; Shenkarev, ZO; Thor, MG; Berkut, AA; Myshkin, MY; Paramonov, AS; Kulbatskii, DS; ... Vassilevski, AA; + view all (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) pp. 4495-4500. 10.1073/pnas.1720185115. Green open access

[img]
Preview
Text
1720185115.full.pdf - Published version

Download (1MB) | Preview

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.

Type: Article
Title: Spider toxin inhibits gating pore currents underlying periodic paralysis
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1720185115
Publisher version: http://dx.doi.org/10.1073/pnas.1720185115
Language: English
Additional information: Copyright © 2018 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Keywords: channelopathy, gating modifier, hypokalemic periodic paralysis, neurotoxin, sodium channel
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/10047297
Downloads since deposit
66Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item