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

Cameron L. Noland, Han Chow Chua, Marc Kschonsak, Stephanie Andrea Heusser, Nina Braun, Timothy Chang, Christine Tam, Jia Tang, Christopher P. Arthur, Claudio Ciferri (), Stephan Alexander Pless () and Jian Payandeh ()
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Cameron L. Noland: Department of Structural Biology, Genentech Inc.
Han Chow Chua: University of Copenhagen
Marc Kschonsak: Department of Structural Biology, Genentech Inc.
Stephanie Andrea Heusser: University of Copenhagen
Nina Braun: University of Copenhagen
Timothy Chang: Department of BioMolecular Resources, Genentech Inc.
Christine Tam: Department of BioMolecular Resources, Genentech Inc.
Jia Tang: Department of Microchemistry, Proteomics & Lipidomics, Genentech Inc.
Christopher P. Arthur: Department of Structural Biology, Genentech Inc.
Claudio Ciferri: Department of Structural Biology, Genentech Inc.
Stephan Alexander Pless: University of Copenhagen
Jian Payandeh: Department of Structural Biology, Genentech Inc.

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Unlike classical voltage-gated sodium (NaV) channels, NaX has been characterized as a voltage-insensitive, tetrodotoxin-resistant, sodium (Na+)-activated channel involved in regulating Na+ homeostasis. However, NaX remains refractory to functional characterization in traditional heterologous systems. Here, to gain insight into its atypical physiology, we determine structures of the human NaX channel in complex with the auxiliary β3-subunit. NaX 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 NaX. 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 NaX-QTT channel construct is non-selective among monovalent cations, inhibited by extracellular calcium, and sensitive to classical NaV channel blockers, including tetrodotoxin. Our findings highlight a functional diversity across the NaV channel scaffold, reshape our understanding of NaX physiology, and provide a template to demystify recalcitrant ion channels.

Date: 2022
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DOI: 10.1038/s41467-022-28984-4

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