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Structure-guided unlocking of Na reveals a non-selective tetrodotoxin-sensitive cation channel

Nature Communications, ISSN: 2041-1723, Vol: 13, Issue: 1, Page: 1416
2022
  • 14
    Citations
  • 0
    Usage
  • 24
    Captures
  • 3
    Mentions
  • 2
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    14
  • Captures
    24
  • Mentions
    3
    • References
      3
      • 3
  • Social Media
    2
    • Shares, Likes & Comments
      2
      • Facebook
        2

Article Description

Unlike classical voltage-gated sodium (Na) channels, Na has been characterized as a voltage-insensitive, tetrodotoxin-resistant, sodium (Na)-activated channel involved in regulating Na homeostasis. However, Na remains refractory to functional characterization in traditional heterologous systems. Here, to gain insight into its atypical physiology, we determine structures of the human Na channel in complex with the auxiliary β3-subunit. Na reveals structural alterations within the selectivity filter, voltage sensor-like domains, and pore module. We do not identify an extracellular Na-sensor or any evidence for a Na-based activation mechanism in Na. Instead, the S6-gate remains closed, membrane lipids fill the central cavity, and the domain III-IV linker restricts S6-dilation. We use protein engineering to identify three pore-wetting mutations targeting the hydrophobic S6-gate that unlock a robust voltage-insensitive leak conductance. This constitutively active Na-QTT channel construct is non-selective among monovalent cations, inhibited by extracellular calcium, and sensitive to classical Na channel blockers, including tetrodotoxin. Our findings highlight a functional diversity across the Na channel scaffold, reshape our understanding of Na physiology, and provide a template to demystify recalcitrant ion channels.

Bibliographic Details

Noland, Cameron L; Chua, Han Chow; Kschonsak, Marc; Heusser, Stephanie Andrea; Braun, Nina; Chang, Timothy; Tam, Christine; Tang, Jia; Arthur, Christopher P; Ciferri, Claudio; Pless, Stephan Alexander; Payandeh, Jian

Springer Science and Business Media LLC

Chemistry; Biochemistry, Genetics and Molecular Biology; Multidisciplinary; Physics and Astronomy

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