Spider toxin inhibits gating pore currents underlying periodic paralysis

Area of Science:

• Neuroscience
• Molecular Biology
• Biophysics

Background:

• Gating pore currents in voltage-sensing domains (VSDs) of skeletal muscle sodium channels (Na_V1.4) are implicated in hypokalemic periodic paralysis (HypoPP) type 2.
• Gating modifier toxins interact with VSDs, offering a potential therapeutic avenue for ion channelopathies.

Purpose of the Study:

• To investigate if gating modifier toxins can block pathogenic gating pore currents.
• To identify specific toxins and their binding sites on Na_V1.4 VSDs.

Main Methods:

• Utilized a crab spider toxin, Hm-3, from *Heriaeus melloteei*.
• Investigated inhibition of gating pore currents caused by HypoPP-associated mutations.
• Employed Nuclear Magnetic Resonance (NMR) studies to elucidate toxin-VSD interactions.

Main Results:

• Hm-3 demonstrated inhibition of gating pore currents linked to specific Na_V1.4 VSD-I mutations found in HypoPP patients.
• NMR revealed Hm-3 binding to VSD-I via hydrophobic and electrostatic interactions with the S3b helix and S3-S4 loop.
• Identified VSD-I as a specific neurotoxin binding site on sodium channels.

Conclusions:

• Hm-3 is a potent inhibitor of pathogenic gating pore currents in Na_V1.4.
• The findings highlight VSD-I as a target for neurotoxin binding.
• Gating modifier toxins represent promising therapeutic leads for HypoPP treatment.