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ASIC1a is the most abundant subunit in the central nervous system and forms homomeric channels permeable to Na\n                    <jats:sup>+<\/jats:sup>\n                    and Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , 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\u2013function studies on ASIC.\n                  <\/jats:p>","DOI":"10.1038\/s41594-026-01845-0","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T09:01:49Z","timestamp":1784192509000},"page":"1171-1182","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Conformational plasticity of human acid-sensing ion channel 1a"],"prefix":"10.1038","volume":"33","author":[{"given":"James","family":"Cahill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7290-5648","authenticated-orcid":false,"given":"Kimberly A.","family":"Hartfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie Andrea","family":"Heusser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2749-885X","authenticated-orcid":false,"given":"Nadine","family":"Ritter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mette Homann","family":"Poulsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Yoshioka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6654-114X","authenticated-orcid":false,"given":"Stephan Alexander","family":"Pless","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5440-2289","authenticated-orcid":false,"given":"Isabelle","family":"Baconguis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"1845_CR1","doi-asserted-by":"publisher","first-page":"8961","DOI":"10.1073\/pnas.1407018111","volume":"111","author":"J Du","year":"2014","unstructured":"Du, J. et al. 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