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

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

eLife, 2022-08, Vol.11 [Periódico revisado por pares]

eLife Sciences Publications Ltd

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  • Título:
    Prolonged β-adrenergic stimulation disperses ryanodine receptor clusters in cardiomyocytes and has implications for heart failure
  • Autor: 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
  • Assuntos: calcium sparks ; cardiomyocytes ; Cell Biology ; heart failure ; phosphorylation ; Research Advance ; ryanodine receptors ; β-adrenergic stimulation
  • É parte de: eLife, 2022-08, Vol.11
  • Notas: ObjectType-Article-1
    SourceType-Scholarly Journals-1
    ObjectType-Feature-2
    content type line 23
  • Descrição: Ryanodine receptors (RyRs) exhibit dynamic arrangements in cardiomyocytes, and we previously showed that ‘dispersion’ of RyR clusters disrupts Ca 2+ homeostasis during heart failure (HF) (Kolstad 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 hr triggered progressive fragmentation of RyR clusters. Pharmacological inhibition of Ca 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 2+ spark fidelity and magnitude, and slowed release kinetics from Ca 2+ 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 Ca 2+ waves. However, during HF, RyR dispersion was linked to impaired Ca 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.
  • Editor: eLife Sciences Publications Ltd
  • Idioma: Inglês;Norueguês
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  • Realização: ABCD-USP USP   Logos de Redes Sociais: Freepik

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