{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T20:28:02Z","timestamp":1786998482699,"version":"build-2736575974"},"reference-count":52,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T00:00:00Z","timestamp":1746403200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>\n                      Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited stress\u2010induced arrhythmogenic disease often caused by point variants in the cardiac ryanodine receptor (RyR2) that enhance diastolic sarcoplasmic reticulum (SR) Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak. These RyR2 variants cluster in three hot\u2010spots (N\u2010terminal, central and C\u2010terminal domains). We previously demonstrated a pathologic diastolic RyR2 conformation in heart failure, oxidative stress and CaMKII phosphorylation exhibiting a trilogy of effects: (1) reduced calmodulin (CaM)\u2010RyR2 affinity, (2) enhanced unzipping peptide (DPc10) binding and (3) elevated diastolic SR Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak that are dantrolene\u2010sensitive. Here we test whether this pathological trilogy occurs in CPVT knock\u2010in (KI) mice bearing N\u2010terminal (R176Q\/+), central (R2474S\/+) and C\u2010terminal variants (R4496C\/+). Isolated saponin\u2010permeabilized ventricular myocytes from all three KI mice exhibited unaltered baseline CaM and DPc10 binding to RyR2\n                      <jats:italic>versus<\/jats:italic>\n                      wild\u2010type (WT) myocytes. However cAMP\u2010induced protein kinase A (PKA)\u2010dependent RyR2 phosphorylation revealed the pathological trilogy, but only in R176Q and R2474S KI myocytes. That contrasts with WT and R4496C KI myocytes where cAMP enhanced SR Ca\n                      <jats:sup>2+<\/jats:sup>\n                      leak without altering either CaM\u2010 or DPc10\u2010RyR2 affinity. We conclude that CPVT\u2010linked RyR2 variants at baseline may not exhibit the pathological diastolic trilogy above, but that trilogy is induced by PKA activation only in N\u2010terminal and central domain CPVT variants. Thus the mechanism of arrhythmogenic RyR2 leak in pore domain variants (e.g. R4496C) may not involve the same pathological conformational changes as in N\u2010terminal and central domain variants. This may inform which specific CPVT\u2010linked RyR2 variants may benefit from therapeutic strategies that target this pathological trilogy conformation.\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\/tjp16673-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>We tested whether CPVT\u2010linked RyR2 variants in the N\u2010terminal (R176Q\/+), central (R2474S\/+) and C\u2010terminal\/pore (R4496C\/+) domains mimic a pathologic trilogy of reduced CaM affinity, enhanced DPc10 peptide binding and arrhythmogenic leaky RyR2.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>At baseline, none of these RyR2 variant knock\u2010in ventricular myocytes exhibited the above trilogy that is seen with heart failure, oxidative stress and CaMKII activation.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>However PKA activation by cAMP promotes that pathological trilogy, but only in the N\u2010terminal and central domain variant myocytes, not the pore domain variant.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Targeted therapies may need to be different for different CPVT\u2010linked variants.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1113\/jp288499","type":"journal-article","created":{"date-parts":[[2025,5,5]],"date-time":"2025-05-05T03:28:48Z","timestamp":1746415728000},"page":"6752-6770","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Catecholaminergic polymorphic ventricular tachycardia\u2013linked ryanodine receptor variants exhibit domain\u2010specific calcium leak and calmodulin affinity properties"],"prefix":"10.1113","volume":"604","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5704-3576","authenticated-orcid":false,"given":"Hitoshi","family":"Uchinoumi","sequence":"first","affiliation":[{"name":"Department of Pharmacology University of California Davis California USA"},{"name":"Department of Medicine and Clinical Science Division of Cardiology Yamaguchi University Graduate School of Medicine Ube Yamaguchi Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqiong","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivanita","family":"Stefanon","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis California USA"},{"name":"Department of Physiological Sciences Federal University of Espirito Santo  Vitoria Espirito Santo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo Hertel","family":"Ribeiro","sequence":"additional","affiliation":[{"name":"Department of Pharmacology University of California Davis California USA"},{"name":"Department of Physiological Sciences Federal University of Espirito Santo  Vitoria Espirito Santo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bengt","family":"Svensson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology and Biophysics University of Minnesota Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5044-672X","authenticated-orcid":false,"given":"Xander H. 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