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The calcium release is enhanced through \u201ccoupled gating\u201d, when the activation of one channel promotes the opening of its neighbours. Here, we determine high-resolution structures of RyR1 in native sarcoplasmic reticulum membranes by cryo-EM\/ET, capturing the conformations along the activation pathway and corner-to-corner interfaces between adjacent RyR1 receptors. Compared with purified RyR1s, receptors in native membranes follow an activation pathway with reduced cytosolic-shell tilt and greater consecutive in-plane rotation. Activation-induced rotation remodels the inter-receptor interface, lowering the energy barrier to the cooperative opening of the receptor cluster. Our analysis demonstrates how the native membrane receptor lattice influences ion channel cluster dynamics and provides a mechanistic framework for understanding calcium signaling in muscle.<\/jats:p>","DOI":"10.1038\/s41467-026-75504-9","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T09:02:31Z","timestamp":1790240551000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ligand-induced activation of RyR1 in native membranes"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6849-4825","authenticated-orcid":false,"given":"Vasilii","family":"Mikirtumov","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Golusik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifeng","family":"Huo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0760-6828","authenticated-orcid":false,"given":"Thiemo","family":"Sprink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikita","family":"Balyschew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7694-7362","authenticated-orcid":false,"given":"Christoph","family":"Diebolder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9858-4742","authenticated-orcid":false,"given":"Shuguang","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhay","family":"Kotecha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3550-6274","authenticated-orcid":false,"given":"Mikhail","family":"Kudryashev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"75504_CR1","first-page":"176","volume":"25","author":"A Sandow","year":"1952","unstructured":"Sandow, A. 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