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Structural and Functional Characterization of a Novel Scorpion Toxin that Inhibits NaV1.8 via Interactions With the
Kiran George1, Diego Lopez-Mateos2,3, Tarek Mohamed Abd El-Aziz4,5,6
1Department of Biology, University of Oklahoma, Norman, OK, United States.
Frontiers in Pharmacology
|June 6, 2022
Summary
A novel toxin, NaTx36, inhibits pain signals by altering voltage-gated sodium channel NaV1.8 gating. This discovery offers new insights into pain mechanisms and potential drug targets.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Voltage-gated sodium channel NaV1.8 is crucial for pain signal transmission.
- Understanding NaV1.8 gating mechanisms is key for developing new pain therapeutics.
- Toxin-predator interactions offer unique models for studying ion channel function.
Purpose of the Study:
- To investigate the molecular mechanisms of NaV1.8 gating using a novel toxin.
- To identify specific residues and interactions involved in toxin-mediated channel inhibition.
- To explore the structure-activity relationship of NaTx36 and its effect on NaV1.8.
Main Methods:
- Screening of synthetic peptide toxins from bark scorpion venom.
- Electrophysiological recording of Na+ currents from recombinant grasshopper mouse NaV1.8 (OtNaV1.8).
- Site-directed mutagenesis and computational modeling to analyze toxin-channel interactions.
Main Results:
- Peptide NaTx36 significantly inhibited OtNaV1.8 currents.
- NaTx36 hyperpolarized channel activation and altered both fast and slow inactivation.
- Mutagenesis identified critical roles for the DI S4 voltage sensor and DII SS2-S6 pore loop residues.
- Computational models revealed unexpected toxin interactions with the DII S5-SS1 pore loop.
Conclusions:
- NaTx36 is a potent inhibitor of NaV1.8, modulating its gating properties.
- Specific interactions involving the DI S4 voltage sensor and DII pore loop are essential for NaTx36's inhibitory action.
- This study provides novel tools and insights into NaV1.8 structure-function relationships and pain modulation.
Keywords:
AZ bark scorpionNaTx36Nav1.8grasshopper miceneurotoxinslow inactivationvenomvoltage-gated sodium channelMore Related Videos
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