Critical role of extracellular loops in differential modulations of TTX-sensitive and TTX-resistant Nav channels

Significance Voltage-gated sodium (Nav) channels are critical regulators of membrane excitability and serve as important therapeutic targets for treating arrhythmia, epilepsy, and pain. Nav1.5, Nav1.8, and Nav1.9, which cannot be blocked by tetrodotoxin (TTX) below micromolar concentrations, are classified as TTX-resistant (TTXr). β1 is absent in the cryo-electron microscopy (cryo-EM) three-dimensional (3D) reconstruction when coexpressed with Nav1.5 or Nav1.8, but always present in TTX-sensitive (TTXs) Nav subtypes. In this study, we reveal several structural elements that underlie the differential TTX and β1 affinities between TTXr and TTXs Nav channels. These findings provide valuable insights for developing subtype-selective Nav-targeting drugs.

• Publication year

  2025

• Venue

  Proceedings of the National Academy of Sciences of the United States of America

• Publication date

  2025-08-06

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1073/pnas.2510355122PMID 40768348PMCID 12358880
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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