Key result
Isoproterenol mobilizes CaMKIIδ, shortening its distance to Z-lines by ~28% and RyRs by ~12%.
Why the study?
It was unclear how CaMKIIδ is spatially recruited and anchored to RyRs to achieve functional regulation of Ca2+ release in cardiomyocytes.
Following β-adrenergic stimulation, activated CaMKIIδ undergoes targeted nanoscale translocation into the RyR nanodomain to facilitate receptor activation, a process dependent on AKAP18δ and an intact microtubular network.
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.
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Bergan-Dahl et al. (2025) studied this question. Isoproterenol vs. Basal condition was evaluated on Distance from Z-lines and RyRs to the nearest CaMKIIδ. Local mobilization of CaMKIIδ by isoproterenol decreased the distance from Z-lines and RyRs to the nearest CaMKIIδ by 28% and 12%, respectively.
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