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Spider toxin inhibits gating pore currents underlying periodic paralysis
- Source :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Year :
- 2018
- Publisher :
- National Academy of Sciences, 2018.
-
Abstract
- Significance Voltage-gated ion channels contain domains that have discrete functionalities. The central pore domain allows current flow and provides ion selectivity, whereas peripherally located voltage-sensing domains (VSDs) are needed for voltage-dependent gating. Certain mutations trigger a leak current through VSDs, known as gating pore current. Hypokalemic periodic paralysis (HypoPP) type 2 is caused by mutations in the skeletal muscle voltage-gated sodium channel NaV1.4 that neutralize positive charges in S4 voltage-sensing segments of VSDs. We show that Hm-3 toxin from the crab spider Heriaeus melloteei inhibits gating pore currents through such mutant channels. We propose that Hm-3 and similar toxins may constitute useful hits in developing gating pore current inhibitors and HypoPP therapy.<br />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.
- Subjects :
- 0301 basic medicine
hypokalemic periodic paralysis
Neurotoxins
Mutation, Missense
Spider Venoms
Gating
Protein Structure, Secondary
03 medical and health sciences
Xenopus laevis
channelopathy
Channelopathy
medicine
Neurotoxin
Animals
Humans
NAV1.4 Voltage-Gated Sodium Channel
Ion channel
Multidisciplinary
Chemistry
Sodium channel
Periodic paralysis
Depolarization
neurotoxin
gating modifier
Biological Sciences
medicine.disease
Spider toxin
3. Good health
030104 developmental biology
HEK293 Cells
Amino Acid Substitution
Biophysics
Female
Ion Channel Gating
Paralysis, Hyperkalemic Periodic
Neuroscience
sodium channel
Subjects
Details
- Language :
- English
- ISSN :
- 10916490 and 00278424
- Volume :
- 115
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....2cbd146f10ccda3c469e9fb5df178df0