{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T15:27:43Z","timestamp":1788276463609,"version":"build-2803163510"},"reference-count":61,"publisher":"Wiley","issue":"17","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["3917\/2\u20101"],"award-info":[{"award-number":["3917\/2\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Ryanodine receptors (RyRs) are Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      \u2010release channels of the sarcoplasmic reticulum. Because uncontrolled Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      \u2010release underlies several muscle and cardiac disorders, pharmacological inhibition of RyRs represents an attractive therapeutic strategy. Natural peptide toxins have provided valuable molecular templates for inhibitor design, with calcins being a particularly promising group. Calcins bind RyRs with high specificity, but, instead of producing the desired full channel block, they stabilize subconductance states that promote Ca\n                      <jats:sup>2<\/jats:sup>\n                      <jats:sup>+<\/jats:sup>\n                      leak. Given the mechanistic similarity between calcins\u2019 action and the well\u2010known charybdotoxin (ChTX)\u2010mediated K\n                      <jats:sup>+<\/jats:sup>\n                      channel blockade, we examined whether ChTX showed functional cross\u2010reactivity with RyR channels. Single\u2010channel recordings were performed on skeletal muscle RyRs reconstituted into lipid bilayers. ChTX induced long\u2010lasting (&gt;0.5\u00a0s) closed events (LLCEs) in a voltage\u2010dependent manner with an apparent\n                      <jats:italic>K<\/jats:italic>\n                      <jats:sub>d<\/jats:sub>\n                      of 85\u00a0n\n                      <jats:sc>m<\/jats:sc>\n                      at +60\u00a0mV. Under these conditions, channels spent \u223c10\u00a0s\u00a0min\n                      <jats:sup>\u22121<\/jats:sup>\n                      in the LLCE state. Notably, isosteric substitution of K27, which is essential for K\n                      <jats:sup>+<\/jats:sup>\n                      channel block, retained RyR inhibition, indicating a pore interaction mechanistically distinct from that described in K\n                      <jats:sup>+<\/jats:sup>\n                      channels. Cardiac RyRs were similarly affected by the K27N variant. Guided by\n                      <jats:italic>in silico<\/jats:italic>\n                      docking to the RyR cryo\u2010electron microscopy structure, we mapped the ChTX\u2010RyR interaction surface using five additional ChTX variants, focusing on basic residues. We found that the R25Q and R34Q substitutions abolished LLCE formation, whereas others had no effect or enhanced channel block. These results describe a novel ChTX\u2010RyR interaction mode functionally convergent with calcin peptides, and they also identify K27N ChTX as a selective RyR inhibitor and a promising scaffold for future drug design.\n                      <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                        <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp70761-gra-0001-m.png\">\n                          <jats:alt-text>image<\/jats:alt-text>\n                        <\/jats:graphic>\n                      <\/jats:boxed-text>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Charybdotoxin (ChTX) blocks ryanodine receptor (RyR) single channel currents in bilayer recordings.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Amino acid residues R25 and R34 are essential for the block.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>K27, which is important for K+ channel block, is irrelevant in RyR block; thereby, the K27N ChTX variant represents a RyR\u2010selective blocker.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>ChTX shares a common binding site with calcin peptides in the channel vestibule, outside the gate.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp290985","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T19:01:12Z","timestamp":1786388472000},"page":"7246-7263","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Old dog, new trick: Charybdotoxin as a novel ryanodine receptor blocker"],"prefix":"10.1113","volume":"604","author":[{"given":"Zsuzsanna \u00c9dua","family":"Magyar","sequence":"first","affiliation":[{"name":"Department of Physiology Faculty of Medicine University of Debrecen  Debrecen Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judit","family":"Hevesi","sequence":"additional","affiliation":[{"name":"Department of Orthodontics Faculty of Dentistry University of Debrecen  Debrecen Hungary"},{"name":"Doctoral School of Molecular Medicine University of Debrecen  Debrecen 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