{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:22:00Z","timestamp":1785853320381,"version":"3.56.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"14","license":[{"start":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T00:00:00Z","timestamp":1760054400000},"content-version":"vor","delay-in-days":9,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006095","name":"South-Eastern Norway Regional Health Authority","doi-asserted-by":"publisher","award":["2020054"],"award-info":[{"award-number":["2020054"]}],"id":[{"id":"10.13039\/501100006095","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norwegian Research Council","doi-asserted-by":"publisher","award":["287395"],"award-info":[{"award-number":["287395"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL092097"],"award-info":[{"award-number":["R01HL092097"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"US National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL142282"],"award-info":[{"award-number":["R01HL142282"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>The heartbeat is triggered by the coordinated release of Ca2+ from the ryanodine receptor type-2 (RyR) in cardiomyocytes. Phosphorylation of RyR by Ca2+\/calmodulin-dependent kinase II\u03b4 (CaMKII\u03b4) fine-tunes this process in health, while hyperphosphorylation causes excessive, pathological Ca2+ release. We investigated how CaMKII\u03b4 is spatially recruited and anchored to RyRs to achieve this functional regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We employed confocal and dSTORM microscopy to investigate the macro- and nanoscale distribution of CaMKII\u03b4 across cardiomyocytes, respectively. We linked positional rearrangement of the kinase during \u03b2-adrenergic stimulation (isoproterenol, Iso) to alterations in RyR phosphorylation and function (Ca2+ sparks), and the requirement of the CaMKII\u03b4 anchoring protein AKAP18\u03b4 by knockdown\/knockout. Confocal microscopy revealed that macroscale CaMKII\u03b4 localization was not markedly altered during Iso-treatment, although a narrowing of its distribution around the Z-lines occurred, where the RyR reside. Higher resolution dSTORM imaging confirmed that local mobilization of CaMKII\u03b4 by Iso decreased the distance from Z-lines and RyRs to the nearest CaMKII\u03b4 by 28 and 12%, respectively. Functionally, kinase translocation into the RyR nanodomain was accompanied by increased channel phosphorylation and Ca2+ spark frequency. These actions were dependent on CaMKII\u03b4 activity, since kinase translocation, RyR phosphorylation, and activation were all mimicked by the upstream activator of CaMKII\u03b4 (8-CPT) and prevented by direct CaMKII\u03b4 inhibitors (AIP, N1 peptide). A critical role of AKAP18\u03b4 in this mechanism was supported by immunoprecipitation experiments, which showed greater kinase binding to AKAP18\u03b4 during Iso-stimulation. Furthermore, loss of AKAP18\u03b4 by viral-mediated AKAP18\u03b4 knockdown or knockout prevented CaMKII\u03b4 translocation to Z-lines. Microtubular disruption also blocked CaMKII\u03b4 translocation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, our results indicate that nanoscale movement of CaMKII\u03b4 is closely associated with RyR activation following \u03b2-adrenergic stimulation. This translocation depends on an intact microtubular network and kinase binding to AKAP18\u03b4.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/cvr\/cvaf187","type":"journal-article","created":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T12:09:05Z","timestamp":1760011745000},"page":"2177-2188","source":"Crossref","is-referenced-by-count":4,"title":["Activated CaMKII\u03b4 translocates to the RyR nanodomain in cardiomyocytes"],"prefix":"10.1093","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1145-596X","authenticated-orcid":false,"given":"Anna","family":"Bergan-Dahl","sequence":"first","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathrine R","family":"Carlson","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Laasmaa","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]},{"name":"Laboratory of Systems Biology, Department of Cybernetics, School of Science, Tallinn University of Technology , 12618 Tallinn ,","place":["Estonia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hariharan","family":"Subramanian","sequence":"additional","affiliation":[{"name":"The University Medical Center Hamburg-Eppendorf , D-20246 Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adelle","family":"Basson","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia","family":"Li","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Almira","family":"Hasic","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Lunde","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hege","family":"Ugland","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3802-6690","authenticated-orcid":false,"given":"Ornella","family":"Manfra","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enno","family":"Klussmann","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Centre for Molecular Medicine in the Helmholtz Association (MDC) , 13125 Berlin ,","place":["Germany"]},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Berlin , 10785 Berlin ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Bossuyt","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California Davis , 451 Health Sciences Drive, Davis, CA 95616 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2237-9483","authenticated-orcid":false,"given":"Donald M","family":"Bers","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California Davis , 451 Health Sciences Drive, Davis, CA 95616 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viacheslav O","family":"Nikolaev","sequence":"additional","affiliation":[{"name":"The University Medical Center Hamburg-Eppendorf , D-20246 Hamburg ,","place":["Germany"]},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Hamburg\/Kiel\/L\u00fcbeck , D-20246 Hamburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0511-6112","authenticated-orcid":false,"given":"William E","family":"Louch","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]},{"name":"K.G. Jebsen Centre for Cardiac Research, University of Oslo , 0450 Oslo ,","place":["Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Shen","sequence":"additional","affiliation":[{"name":"Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo , PB 4956, NO-0424 Oslo ,","place":["Norway"]},{"name":"K.G. 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