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| Item Type: | Article |
|---|---|
| Title: | Activated CaMKIIδ translocates to the RyR nanodomain in cardiomyocytes |
| Creators: |
Bergan-Dahl, Anna  ORCID: https://orcid.org/0000-0003-1145-596X, Carlson, Cathrine R., Laasmaa, Martin, Subramanian, Hariharan, Basson, Adelle, Li, Jia, Hasic, Almira, Lunde, Marianne, Ugland, Hege, Manfra, Ornella ORCID: https://orcid.org/0000-0002-3802-6690, Klussmann, Enno ORCID: https://orcid.org/0000-0003-4004-5003, Bossuyt, Julie, Bers, Donald M. ORCID: https://orcid.org/0000-0002-2237-9483, Nikolaev, Viacheslav O., Louch, William E. ORCID: https://orcid.org/0000-0002-0511-6112 and Shen, Xin
|
| Abstract: | AIMS: 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 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 RESULTS: We 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. CONCLUSION: Collectively, 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. |
| Keywords: | CaMKIIδ, RyR, AKAP18δ, Cardiomyocyte, Ca(2+) Homeostasis, Animals, Mice, Rats |
| Source: | Cardiovascular Research |
| ISSN: | 0008-6363 |
| Publisher: | Oxford University Press |
| Volume: | 121 |
| Number: | 14 |
| Page Range: | 2177-2188 |
| Date: | October 2025 |
| Official Publication: | https://doi.org/10.1093/cvr/cvaf187 |
| PubMed: | View item in PubMed |
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