Prolonged [beta]-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure

• Published in: eLife Vol. 11
• Main Authors: Shen, Xin, van den Brink, Jonas, Bergan-Dahl, Anna, Kolstad, Terje R, Norden, Einar S, Hou, Yufeng, Laasmaa, Martin, Aguilar-Sanchez, Yuriana, Quick, Ann P, Espe, Emil KS, Sjaastad, Ivar, Wehrens, Xander HT, Edwards, Andrew G, Soeller, Christian, Louch, William E
• Format: Journal Article
• Language: English
• Published: eLife Science Publications, Ltd 01.08.2022
• Subjects: Calcium-binding proteins; Heart cells; Heart failure; Canada
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.77725

Ryanodine receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that 'dispersion' of RyR clusters disrupts Ca.sup.2+ homeostasis during heart failure (HF) (Kolstad et al., eLife, 2018). Here, we investigated whether prolonged [beta]-adrenergic stimulation, a hallmark of HF, promotes RyR cluster dispersion and examined the underlying mechanisms. We observed that treatment of healthy rat cardiomyocytes with isoproterenol for 1 hr triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of Ca.sup.2+/calmodulin-dependent protein kinase II (CaMKII) reversed these effects, while cluster dispersion was reproduced by specific activation of CaMKII, and in mice with constitutively active Ser2814-RyR. A similar role of protein kinase A (PKA) in promoting RyR cluster fragmentation was established by employing PKA activation or inhibition. Progressive cluster dispersion was linked to declining Ca.sup.2+ spark fidelity and magnitude, and slowed release kinetics from Ca.sup.2+ propagation between more numerous RyR clusters. In healthy cells, this served to dampen the stimulatory actions of [beta]-adrenergic stimulation over the longer term and protect against pro-arrhythmic Ca.sup.2+ waves. However, during HF, RyR dispersion was linked to impaired Ca.sup.2+ release. Thus, RyR localization and function are intimately linked via channel phosphorylation by both CaMKII and PKA, which, while finely tuned in healthy cardiomyocytes, underlies impaired cardiac function during pathology.