{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:16:39Z","timestamp":1753892199404,"version":"3.41.2"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T00:00:00Z","timestamp":1665532800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000274","name":"British Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000274","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>The ryanodine receptor (RyR) is a homotetrameric channel mediating sarcoplasmic reticulum Ca<jats:sup>2+<\/jats:sup> release required for skeletal and cardiac muscle contraction. Mutations in RyR1 and RyR2 lead to life-threatening malignant hyperthermia episodes and ventricular tachycardia, respectively. In this brief report, we use chemical cross-linking to demonstrate that pathogenic RyR1 R163C and RyR2 R169Q mutations reduce N-terminus domain (NTD) tetramerization. Introduction of positively-charged residues (Q168R, M399R) in the NTD-NTD inter-subunit interface normalizes RyR2-R169Q NTD tetramerization. These results indicate that perturbation of NTD-NTD inter-subunit interactions is an underlying molecular mechanism in both RyR1 and RyR2 pathophysiology. Importantly, our data provide proof of concept that stabilization of this critical RyR1\/2 structure-function parameter offers clear therapeutic potential.<\/jats:p>","DOI":"10.3389\/fphys.2022.1032132","type":"journal-article","created":{"date-parts":[[2022,10,12]],"date-time":"2022-10-12T08:21:57Z","timestamp":1665562917000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders"],"prefix":"10.3389","volume":"13","author":[{"given":"Yadan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Camille","family":"Rabesahala de Meritens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Astrid","family":"Beckmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F. 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