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Prolonged β-Adrenergic stimulation and heart failure disperses ryanodine receptor clusters

Shen X, van den Brink J, Bergan-Dahl A, Kolstad TR, Norden ES, Hou Y, Laasmaa M, Aguilar-Sanchez Y, Quick AP, Espe EKS, Sjaastad I, Wehrens XHT, Edwards AG, Soeller C, Louch WE

Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure.

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The heartbeat is triggered by the release of Ca2+ from Ryanodine Receptors (RyRs) within cardiomyocytes. Recent data indicate RyR arrangement is highly malleable. However, mechanisms controlling RyR reorganisation and the subsequent impact on Ca2+ homeostasis remain unclear. Here, we show that prolonged β-adrenergic stimulation causes RyR clusters to disperse, drastically altering the frequency and kinetics of Ca2+ release events called “Ca2+ sparks” in a process that is dependent on CaMKII and PKA. In healthy cells, these compensatory effects protect against arrhythmogenic Ca2+ over-activity. However, during heart failure, RyR hyper-phosphorylation and dispersion impairs Ca2+ release and cardiac performance. Thus, RyR localization and function are intimately linked via channel phosphorylation which, while finely tuned in health, underlies impaired cardiac function during pathology.

RyR: Ryanodine receptors, CRU: Calcium release unit, HF: heart failure, b-AR: b-adrenergic receptor

Elife, 11
PubMed 35913125 DOI 10.7554/eLife.77725

Xin Shen

Postdoctoral fellow

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William (Bill) Louch

Group Leader & Professor

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Institute for Experimental Medical Research

Oslo University Hospital, Ullevål

PB 4956 Nydalen

NO-0424 Oslo

Norway

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