@article {42622,
	title = {Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes},
	journal = {eLife},
	volume = {11},
	year = {2022},
	month = {Jan-08-2022},
	publisher = {eLife},
	address = {eLife},
	abstract = {Ryanodine Receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that {\textquoteright}dispersion{\textquoteright} of RyR clusters disrupts Ca2+\&nbsp;homeostasis during heart failure (HF) (Kolstad\&nbsp;et al., eLife, 2018). Here, we investigated whether prolonged β-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 hour triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of 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 Ca2+\&nbsp;spark fidelity and magnitude, and slowed release kinetics from Ca2+\&nbsp;propagation between more numerous RyR clusters. In healthy cells, this served to dampen the stimulatory actions of β-adrenergic stimulation over the longer term, and protect against pro-arrhythmic Ca2+\&nbsp;waves. However, during HF, RyR dispersion was linked to impaired Ca2+\&nbsp;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.ADD A COMMENT\&nbsp;+Open annotations. The current annotation count on this page is\&nbsp;0.Data availability},
	doi = {10.7554/eLife.77725},
	url = {https://elifesciences.org/articles/77725https://cdn.elifesciences.org/articles/77725/elife-77725-v1.pdfhttps://cdn.elifesciences.org/articles/77725/elife-77725-v1.xml},
	author = {Shen, Xin and van den Brink, Jonas and Bergan-Dahl, Anna and Terje R {Kolstad} and Einar Sjaastad {Norden} and Hou, Yufeng and Laasmaa, Martin and Aguilar-Sanchez, Yuriana and Ann Pepper {Quick} and Emil Knut Stene {Espe} and Sjaastad, Ivar and Xander HT {Wehrens} and Andrew G {Edwards} and Soeller, Christian and William Edward {Louch}}
}
