Inhibition of Sodium Ion Channel Function with Truncated Forms of Batrachotoxin

A novel family of small molecule inhibitors of voltage-gated sodium channels (NaVs) based on the structure of batrachotoxin (BTX), a well-known channel agonist, is described. Protein mutagenesis and electrophysiology experiments reveal the binding site as the inner pore region of the channel, analog...

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Bibliographic Details
Published in:ACS chemical neuroscience 2016-10, Vol.7 (10), p.1463-1468
Main Authors: Toma, Tatsuya, Logan, Matthew M, Menard, Frederic, Devlin, A. Sloan, Du Bois, J
Format: Article
Language:English
Subjects:
Animals
Batrachotoxins - analysis
Batrachotoxins - chemical synthesis
Batrachotoxins - pharmacology
CHO Cells
Cricetulus
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Models, Molecular
Molecular Structure
Muscle Proteins - genetics
Muscle Proteins - metabolism
Mutation
Patch-Clamp Techniques
Rats
Sodium Channel Blockers - chemical synthesis
Sodium Channel Blockers - pharmacology
Sodium Channels - genetics
Sodium Channels - metabolism
Structure-Activity Relationship
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Summary:A novel family of small molecule inhibitors of voltage-gated sodium channels (NaVs) based on the structure of batrachotoxin (BTX), a well-known channel agonist, is described. Protein mutagenesis and electrophysiology experiments reveal the binding site as the inner pore region of the channel, analogous to BTX, alkaloid toxins, and local anesthetics. Homology modeling of the eukaryotic channel based on recent crystallographic analyses of bacterial NaVs suggests a mechanism of action for ion conduction block.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.6b00212