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Peer-reviewedCC BYNature Structural & Molecular Biology

Conformational plasticity of human acid-sensing ion channel 1a

  • James Cahill1,2
  • Kimberly A. Hartfield1,2
  • Stephanie Andrea Heusser3,4,5
  • Nadine Ritter4,5
  • Mette Homann Poulsen4,6
  • Craig Yoshioka7,5
  • Stephan Alexander Pless4,2
  • Isabelle Baconguis8
8 affiliations
  1. 1Vollum Institute, Oregon Health and Science University, Portland, OR, USA
  2. 2Vollum Institute, Oregon Health & Science University, Portland, OR 97239
  3. 3Department of Biomedical and Clinical Sciences, Linköping University, Linkoping, Sweden
  4. 4Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
  5. 5University of Copenhagen, Department of Drug Design and Pharmacology, Jagtvej 160, 100 Copenhagen, Denmark
  6. 6Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR 9729
  7. 7Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR, USA
  8. 8Vollum Institute, Oregon Health and Science University, Portland, OR, USA. [email protected]
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Abstract

Acid-sensing ion channels (ASICs) are typically activated by acidic environments and contribute to nociception and synaptic plasticity. ASIC1a is the most abundant subunit in the central nervous system and forms homomeric channels permeable to Na + and Ca 2+ , making it a compelling therapeutic target for acidotic pathologies including stroke and traumatic brain injury. However, a complete conformational library of human ASIC1a has yet to be described. Here we show that human ASIC1a adopts six major conformations, resolved by cryo-electron microscopy across a pH range between 8.5 and 5.7 and in the presence of a toxin agonist and a gating-modifying amino acid substitution. These major conformations establish linear transmembrane helices to be associated with an open state, delineate mechanistic differences between proton and toxin activation and demonstrate that desensitization involves unexpected conformational diversity in the transmembrane domain. Together, they provide a three-dimensional framework to integrate previous structure–function studies on ASIC.

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Cite

BibTeXRIS
BibTeX
@article{cahill2026conformational,
  title = {{Conformational plasticity of human acid-sensing ion channel 1a}},
  author = {James Cahill and Kimberly A. Hartfield and Stephanie Andrea Heusser and Nadine Ritter and Mette Homann Poulsen and Craig Yoshioka and Stephan Alexander Pless and Isabelle Baconguis},
  journal = {Nature Structural \& Molecular Biology},
  year = {2026},
  month = jul,
  doi = {10.1038/s41594-026-01845-0},
  url = {https://doi.org/10.1038/s41594-026-01845-0},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Conformational plasticity of human acid-sensing ion channel 1a
AU  - James Cahill
AU  - Kimberly A. Hartfield
AU  - Stephanie Andrea Heusser
AU  - Nadine Ritter
AU  - Mette Homann Poulsen
AU  - Craig Yoshioka
AU  - Stephan Alexander Pless
AU  - Isabelle Baconguis
PY  - 2026
DA  - 2026/07/16
JO  - Nature Structural & Molecular Biology
DO  - 10.1038/s41594-026-01845-0
UR  - https://doi.org/10.1038/s41594-026-01845-0
AB  - Acid-sensing ion channels (ASICs) are typically activated by acidic environments and contribute to nociception and synaptic plasticity. ASIC1a is the most abundant subunit in the central nervous system and forms homomeric channels permeable to Na + and Ca 2+ , making it a compelling therapeutic target for acidotic pathologies including stroke and traumatic brain injury. However, a complete conformational library of human ASIC1a has yet to be described. Here we show that human ASIC1a adopts six major conformations, resolved by cryo-electron microscopy across a pH range between 8.5 and 5.7 and in the presence of a toxin agonist and a gating-modifying amino acid substitution. These major conformations establish linear transmembrane helices to be associated with an open state, delineate mechanistic differences between proton and toxin activation and demonstrate that desensitization involves unexpected conformational diversity in the transmembrane domain. Together, they provide a three-dimensional framework to integrate previous structure–function studies on ASIC.
SN  - 1545-9985
SN  - 1545-9993
ER  -