ArticleCardiovascular research2025
Activated CaMKIIδ translocates to the RyR nanodomain in cardiomyocytes.
Article in Cardiovascular research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Exploring the role of CaMKII in exercise-induced cardioprotection.Human cell · 2026Review
- The role of calcium homeostasis dysregulation in allergic rhinitis.Frontiers in immunology · 2026Review
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16 authors.
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Abstract
aimsThe 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 IIδ (CaMKIIδ) fine-tunes this process in health, while hyperphosphorylation causes excessive, pathological Ca2+ release. We investigated how CaMKIIδ is spatially recruited and anchored to RyRs to achieve this functional regulation. METHODS AND
resultsWe employed confocal and dSTORM microscopy to investigate the macro- and nanoscale distribution of CaMKIIδ across cardiomyocytes, respectively. We linked positional rearrangement of the kinase during β-adrenergic stimulation (isoproterenol, Iso) to alterations in RyR phosphorylation and function (Ca2+ sparks), and the requirement of the CaMKIIδ anchoring protein AKAP18δ by knockdown/knockout. Confocal microscopy revealed that macroscale CaMKIIδ 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 CaMKIIδ by Iso decreased the distance from Z-lines and RyRs to the nearest CaMKIIδ 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 CaMKIIδ activity, since kinase translocation, RyR phosphorylation, and activation were all mimicked by the upstream activator of CaMKIIδ (8-CPT) and prevented by direct CaMKIIδ inhibitors (AIP, N1 peptide). A critical role of AKAP18δ in this mechanism was supported by immunoprecipitation experiments, which showed greater kinase binding to AKAP18δ during Iso-stimulation. Furthermore, loss of AKAP18δ by viral-mediated AKAP18δ knockdown or knockout prevented CaMKIIδ translocation to Z-lines. Microtubular disruption also blocked CaMKIIδ translocation.
conclusionCollectively, our results indicate that nanoscale movement of CaMKIIδ is closely associated with RyR activation following β-adrenergic stimulation. This translocation depends on an intact microtubular network and kinase binding to AKAP18δ.
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